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Coronary Artery Disease: HELP
Articles from Estonia
Based on 26 articles published since 2008
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These are the 26 published articles about Coronary Artery Disease that originated from Estonia during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Human Validation of Genes Associated With a Murine Atherosclerotic Phenotype. 2016

Pasterkamp, Gerard / van der Laan, Sander W / Haitjema, Saskia / Foroughi Asl, Hassan / Siemelink, Marten A / Bezemer, Tim / van Setten, Jessica / Dichgans, Martin / Malik, Rainer / Worrall, Bradford B / Schunkert, Heribert / Samani, Nilesh J / de Kleijn, Dominique P V / Markus, Hugh S / Hoefer, Imo E / Michoel, Tom / de Jager, Saskia C A / Björkegren, Johan L M / den Ruijter, Hester M / Asselbergs, Folkert W. ·From the Laboratory of Experimental Cardiology, Division Heart and Lungs (G.P., S.W.v.d.L., S.H., M.A.S., T.B., J.v.S., I.E.H., S.C.A.d.J., H.M.d.R.), Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy (G.P.), and Division Heart and Lungs, Department of Cardiology (F.W.A.), University Medical Center Utrecht, Utrecht, The Netherlands · Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.F.A., J.L.M.B.) · Institut für Schlaganfall- und Demenzforschung (ISD) Klinikum der Universität München, Munich, Germany (M.D., R.M.) · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.) · Department of Neurology, University of Virginia, Charlottesville (B.B.W.) · Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.) · Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., Partner Site Munich Heart Alliance, Munich, Germany (H.S.) · Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.) · Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Leicester, United Kingdom (N.J.S.) · Department of Surgery, National University of Singapore, Singapore (D.P.V.d.K.) · Cardiovascular Research Institute (CVRI), National University Health System, Singapore, Singapore (D.P.V.d.K.) · Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (D.P.V.d.K.) · Department of Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.) · The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom (T.M.) · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (J.L.M.B.) · Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estoni ·Arterioscler Thromb Vasc Biol · Pubmed #27079880.

ABSTRACT: OBJECTIVE: The genetically modified mouse is the most commonly used animal model for studying the pathogenesis of atherosclerotic disease. We aimed to assess if mice atherosclerosis-related genes could be validated in human disease through examination of results from genome-wide association studies. APPROACH AND RESULTS: We performed a systematic review to identify atherosclerosis-causing genes in mice and carried out gene-based association tests of their human orthologs for an association with human coronary artery disease and human large artery ischemic stroke. Moreover, we investigated the association of these genes with human atherosclerotic plaque characteristics. In addition, we assessed the presence of tissue-specific cis-acting expression quantitative trait loci for these genes in humans. Finally, using pathway analyses we show that the putative atherosclerosis-causing genes revealed few associations with human coronary artery disease, large artery ischemic stroke, or atherosclerotic plaque characteristics, despite the fact that the majority of these genes have cis-acting expression quantitative trait loci. CONCLUSIONS: A role for genes that has been observed in mice for atherosclerotic lesion development could scarcely be confirmed by studying associations of disease development with common human genetic variants. The value of murine atherosclerotic models for selection of therapeutic targets in human disease remains unclear.

2 Review Genome-wide significant loci: how important are they? Systems genetics to understand heritability of coronary artery disease and other common complex disorders. 2015

Björkegren, Johan L M / Kovacic, Jason C / Dudley, Joel T / Schadt, Eric E. ·Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York; Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia. Electronic address: johan.bjorkegren@mssm.edu. · Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. ·J Am Coll Cardiol · Pubmed #25720628.

ABSTRACT: Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities.

3 Article PCSK9 Inhibitor causes a decrease in the level of oxidatively modified low-density lipoproteins in patients with coronary artery diseases. 2018

Lankin, V Z / Tikhaze, A K / Viigimaa, M / Chazova, I Е. ·FSBI "National Medical Research Cardiology Center" of the Ministry of Health of the Russian Federation, Moscow, Russia. · Center for Cardiology of Tallinn University of Technology, Tallinn, Estonia. ·Ter Arkh · Pubmed #30701731.

ABSTRACT: AIM: We study the dynamics of oxidatively modified low-density lipoprotein (ox-LDL) content in blood plasma, as well as changes in the activity of key antioxidant enzymes such as Se-containing glutathione peroxidase (GSH-Px) Cu,Zn-superoxide dismutase (SOD) and catalase in erythrocytes of patients with coronary artery disease during treatment with PCSK9 inhibitor (ewolocumab). MATERIALS AND METHODS: The study included 9 men (59 ± 10 years) with coronary artery disease with atherosclerotic lesion at least one main coronary artery according to coronary angiography. Patients took standard therapy before taking the study, everyone took the maximum tolerated dose of statins. Since the target cholesterol levels of low-density lipoprotein cholesterol (LDL-C) were not achieved during the statin therapy, patients were prescribed lipid-lowering therapy with the inclusion of the inhibitor PCSK9-emocoucumab from Amgen 420 mg once a month. The content of lipid metabolism indices was determined by standard biochemical methods. The level of ox-LDL in the blood plasma was determined by the immunochemical method. The activity of antioxidant enzymes was determined in blood erythrocytes using biochemical techniques. RESULTS: Cholesterol-lowering drug of the new type - inhibitor protein convertase subtilisin/kexin type 9 (PCSK9) evolocumab (Amgen) not only effectively lowers the level of cholesterol in low density lipoprotein (LDL), but also significantly reduces the content of oxdatively modified LDL in blood plasma. Unlike statins, the inhibitor of PCSK9 does not cause a decrease in the activity of antioxidant enzymes of the blood. CONCLUSION: PCSK9 inhibitor has no effect on the parameters of oxidative stress.

4 Article Functional regulatory mechanism of smooth muscle cell-restricted LMOD1 coronary artery disease locus. 2018

Nanda, Vivek / Wang, Ting / Pjanic, Milos / Liu, Boxiang / Nguyen, Trieu / Matic, Ljubica Perisic / Hedin, Ulf / Koplev, Simon / Ma, Lijiang / Franzén, Oscar / Ruusalepp, Arno / Schadt, Eric E / Björkegren, Johan L M / Montgomery, Stephen B / Snyder, Michael P / Quertermous, Thomas / Leeper, Nicholas J / Miller, Clint L. ·Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California, United States of America. · Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Biology, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States of America. · Clinical Gene Networks AB, Stockholm, Sweden. · Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia. · Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia. · Center for Public Health Genomics, Department of Public Health Sciences, Department of Biochemistry and Molecular Genetics, and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America. ·PLoS Genet · Pubmed #30444878.

ABSTRACT: Recent genome-wide association studies (GWAS) have identified multiple new loci which appear to alter coronary artery disease (CAD) risk via arterial wall-specific mechanisms. One of the annotated genes encodes LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle-containing tissues such as the artery wall. However, it is still unknown whether LMOD1 is the causal gene at this locus and also how the associated variants alter LMOD1 expression/function and CAD risk. Using epigenomic profiling we recently identified a non-coding regulatory variant, rs34091558, which is in tight linkage disequilibrium (LD) with the lead CAD GWAS variant, rs2820315. Herein we demonstrate through expression quantitative trait loci (eQTL) and statistical fine-mapping in GTEx, STARNET, and human coronary artery smooth muscle cell (HCASMC) datasets, rs34091558 is the top regulatory variant for LMOD1 in vascular tissues. Position weight matrix (PWM) analyses identify the protective allele rs34091558-TA to form a conserved Forkhead box O3 (FOXO3) binding motif, which is disrupted by the risk allele rs34091558-A. FOXO3 chromatin immunoprecipitation and reporter assays show reduced FOXO3 binding and LMOD1 transcriptional activity by the risk allele, consistent with effects of FOXO3 downregulation on LMOD1. LMOD1 knockdown results in increased proliferation and migration and decreased cell contraction in HCASMC, and immunostaining in atherosclerotic lesions in the SMC lineage tracing reporter mouse support a key role for LMOD1 in maintaining the differentiated SMC phenotype. These results provide compelling functional evidence that genetic variation is associated with dysregulated LMOD1 expression/function in SMCs, together contributing to the heritable risk for CAD.

5 Article Inverse relations of serum phosphatidylcholines and lysophosphatidylcholines with vascular damage and heart rate in patients with atherosclerosis. 2018

Paapstel, K / Kals, J / Eha, J / Tootsi, K / Ottas, A / Piir, A / Jakobson, M / Lieberg, J / Zilmer, M. ·Institute of Biomedicine and Translational Medicine, Department of Biochemistry, Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia; Endothelial Centre, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. Electronic address: paapstel@outlook.com. · Institute of Biomedicine and Translational Medicine, Department of Biochemistry, Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia; Endothelial Centre, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia; Department of Surgery, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. · Endothelial Centre, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia; Department of Cardiology, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. · Endothelial Centre, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. · Institute of Biomedicine and Translational Medicine, Department of Biochemistry, Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia. · Department of Radiology, Tartu University Hospital, Tartu 51014, Estonia. · Department of Surgery, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. · Institute of Biomedicine and Translational Medicine, Department of Biochemistry, Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia; Endothelial Centre, University of Tartu, 8 Puusepa Street, Tartu 51014, Estonia. ·Nutr Metab Cardiovasc Dis · Pubmed #28986077.

ABSTRACT: BACKGROUND AND AIMS: The rapidly growing discipline of lipidomics allows the study of a wide spectrum of lipid species in body fluids and provides new insights into the pathogenesis of cardiovascular disease. We investigated serum phosphatidylcholine (PC) and lysophosphatidylcholine (lysoPC) species in relation to arterial stiffness, hemodynamics, and endothelial dysfunction in symptomatic patients with atherosclerosis and in healthy controls. METHODS AND RESULTS: Thirty-two patients with peripheral arterial disease (age 61.7 ± 9.0 years), 52 patients with coronary artery disease (age 63.2 ± 9.2 years), and 40 apparently healthy controls (age 60.3 ± 7.1 years) were studied. Serum levels of 90 glycerophospholipids were determined with the AbsoluteIDQ™ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria). The technique of applanation tonometry was used for non-invasive pulse wave analysis and carotid-femoral pulse wave velocity (cf-PWV) assessment. Decreased serum levels of several individual PC and lysoPC species (e.g., PC aa C28:1, PC aa C30:0, PC aa C32:2, PC ae C30:0 and PC ae C34:2, lysoPC a C18:2) were observed for the patient groups in comparison to the healthy subjects. In addition, a considerable number of PCs and lysoPCs were inversely related to either cf-PWV, heart rate, asymmetric dimethylarginine (ADMA) or ADMA/arginine for patients with symptomatic atherosclerosis but not for the controls. CONCLUSION: We found altered relationships between PC and lysoPC profiles, inflammation, and arterial function in atherosclerotic patients, compared to healthy subjects.

6 Article Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation. 2017

Vilne, Baiba / Skogsberg, Josefin / Foroughi Asl, Hassan / Talukdar, Husain Ahammad / Kessler, Thorsten / Björkegren, Johan L M / Schunkert, Heribert. ·Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. · Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. · Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, 141 57 Huddinge, Sweden. · Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Estonia; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York, New York, USA; Clinical Gene Networks AB, Stockholm, Sweden. Electronic address: johan.bjorkegren@mssm.edu. · Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany; DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. Electronic address: schunkert@dhm.mhn.de. ·Atherosclerosis · Pubmed #29100060.

ABSTRACT: BACKGROUND AND AIMS: Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation. METHODS: To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach. RESULTS: During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses. CONCLUSIONS: Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes.

7 Article Exome-wide association study of plasma lipids in >300,000 individuals. 2017

Liu, Dajiang J / Peloso, Gina M / Yu, Haojie / Butterworth, Adam S / Wang, Xiao / Mahajan, Anubha / Saleheen, Danish / Emdin, Connor / Alam, Dewan / Alves, Alexessander Couto / Amouyel, Philippe / Di Angelantonio, Emanuele / Arveiler, Dominique / Assimes, Themistocles L / Auer, Paul L / Baber, Usman / Ballantyne, Christie M / Bang, Lia E / Benn, Marianne / Bis, Joshua C / Boehnke, Michael / Boerwinkle, Eric / Bork-Jensen, Jette / Bottinger, Erwin P / Brandslund, Ivan / Brown, Morris / Busonero, Fabio / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Y Eugene / Chen, Yii-Der Ida / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Connell, John M / Cucca, Francesco / Cupples, L Adrienne / Damrauer, Scott M / Davies, Gail / Deary, Ian J / Dedoussis, George / Denny, Joshua C / Dominiczak, Anna / Dubé, Marie-Pierre / Ebeling, Tapani / Eiriksdottir, Gudny / Esko, Tõnu / Farmaki, Aliki-Eleni / Feitosa, Mary F / Ferrario, Marco / Ferrieres, Jean / Ford, Ian / Fornage, Myriam / Franks, Paul W / Frayling, Timothy M / Frikke-Schmidt, Ruth / Fritsche, Lars G / Frossard, Philippe / Fuster, Valentin / Ganesh, Santhi K / Gao, Wei / Garcia, Melissa E / Gieger, Christian / Giulianini, Franco / Goodarzi, Mark O / Grallert, Harald / Grarup, Niels / Groop, Leif / Grove, Megan L / Gudnason, Vilmundur / Hansen, Torben / Harris, Tamara B / Hayward, Caroline / Hirschhorn, Joel N / Holmen, Oddgeir L / Huffman, Jennifer / Huo, Yong / Hveem, Kristian / Jabeen, Sehrish / Jackson, Anne U / Jakobsdottir, Johanna / Jarvelin, Marjo-Riitta / Jensen, Gorm B / Jørgensen, Marit E / Jukema, J Wouter / Justesen, Johanne M / Kamstrup, Pia R / Kanoni, Stavroula / Karpe, Fredrik / Kee, Frank / Khera, Amit V / Klarin, Derek / Koistinen, Heikki A / Kooner, Jaspal S / Kooperberg, Charles / Kuulasmaa, Kari / Kuusisto, Johanna / Laakso, Markku / Lakka, Timo / Langenberg, Claudia / Langsted, Anne / Launer, Lenore J / Lauritzen, Torsten / Liewald, David C M / Lin, Li An / Linneberg, Allan / Loos, Ruth J F / Lu, Yingchang / Lu, Xiangfeng / Mägi, Reedik / Malarstig, Anders / Manichaikul, Ani / Manning, Alisa K / Mäntyselkä, Pekka / Marouli, Eirini / Masca, Nicholas G D / Maschio, Andrea / Meigs, James B / Melander, Olle / Metspalu, Andres / Morris, Andrew P / Morrison, Alanna C / Mulas, Antonella / Müller-Nurasyid, Martina / Munroe, Patricia B / Neville, Matt J / Nielsen, Jonas B / Nielsen, Sune F / Nordestgaard, Børge G / Ordovas, Jose M / Mehran, Roxana / O'Donnell, Christoper J / Orho-Melander, Marju / Molony, Cliona M / Muntendam, Pieter / Padmanabhan, Sandosh / Palmer, Colin N A / Pasko, Dorota / Patel, Aniruddh P / Pedersen, Oluf / Perola, Markus / Peters, Annette / Pisinger, Charlotta / Pistis, Giorgio / Polasek, Ozren / Poulter, Neil / Psaty, Bruce M / Rader, Daniel J / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Reiner, Alex P / Renström, Frida / Rich, Stephen S / Ridker, Paul M / Rioux, John D / Robertson, Neil R / Roden, Dan M / Rotter, Jerome I / Rudan, Igor / Salomaa, Veikko / Samani, Nilesh J / Sanna, Serena / Sattar, Naveed / Schmidt, Ellen M / Scott, Robert A / Sever, Peter / Sevilla, Raquel S / Shaffer, Christian M / Sim, Xueling / Sivapalaratnam, Suthesh / Small, Kerrin S / Smith, Albert V / Smith, Blair H / Somayajula, Sangeetha / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Stirrups, Kathleen E / Stitziel, Nathan / Strauch, Konstantin / Stringham, Heather M / Surendran, Praveen / Tada, Hayato / Tall, Alan R / Tang, Hua / Tardif, Jean-Claude / Taylor, Kent D / Trompet, Stella / Tsao, Philip S / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / van Zuydam, Natalie R / Varbo, Anette / Varga, Tibor V / Virtamo, Jarmo / Waldenberger, Melanie / Wang, Nan / Wareham, Nick J / Warren, Helen R / Weeke, Peter E / Weinstock, Joshua / Wessel, Jennifer / Wilson, James G / Wilson, Peter W F / Xu, Ming / Yaghootkar, Hanieh / Young, Robin / Zeggini, Eleftheria / Zhang, He / Zheng, Neil S / Zhang, Weihua / Zhang, Yan / Zhou, Wei / Zhou, Yanhua / Zoledziewska, Magdalena / Anonymous1331021 / Anonymous1341021 / Anonymous1351021 / Anonymous1361021 / Anonymous1371021 / Howson, Joanna M M / Danesh, John / McCarthy, Mark I / Cowan, Chad A / Abecasis, Goncalo / Deloukas, Panos / Musunuru, Kiran / Willer, Cristen J / Kathiresan, Sekar. ·Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK. · Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · ICDDR, B, Dhaka, Bangladesh. · Imperial College London, London, UK. · Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France. · VA Palo Alto Health Care System, Palo Alto, California, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. · Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. · Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. · Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. · Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. · Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy. · The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK. · NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. · The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA. · Medical Department, Lillebaelt Hospital, Vejle, Denmark. · NHLBI Framingham Heart Study, Framingham, Massachusetts, USA. · Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. · Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. · Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Psychology, University of Edinburgh, Edinburgh, UK. · Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. · Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Montreal Heart Institute, Montreal, Quebec, Canada. · Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada. · Université de Montréal, Montreal, Quebec, Canada. · Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland. · The Icelandic Heart Association, Kopavogur, Iceland. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. · Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA. · Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK. · Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China. · National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA. · Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway. · St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. · Department of Cardiology, Peking University First Hospital, Beijing, China. · K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. · Department of Health Sciences, University of Iceland, Reykjavik, Iceland. · The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark. · Steno Diabetes Center, Gentofte, Denmark. · National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark. · Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. · The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. · UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Minerva Foundation Institute for Medical Research, Helsinki, Finland. · National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark. · Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark. · Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Research Center for Prevention and Health, Copenhagen, Denmark. · The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. · Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany. · DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA. · Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · G3 Pharmaceuticals, Lexington, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Institute of Molecular Medicine FIMM, University of Helsinki, Finland. · Faculty of Medicine, University of Split, Split, Croatia. · Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · International Centre for Circulatory Health, Imperial College London, London, UK. · Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA. · Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biobank Research, Umeå University, Umeå, Sweden. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. · Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Saw Swee Hock School of Public Health, National University of Singapore, Singapore. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK. · Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK. · Department of Haematology, University of Cambridge, Cambridge, UK. · Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA. · IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. · Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. · Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. · Dasman Diabetes Institute, Dasman, Kuwait. · Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. · Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia. · The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Atlanta VA Medical Center, Decatur, Georgia, USA. · Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA. · Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. · Yale College, Yale University, New Haven, Connecticut, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #29083408.

ABSTRACT: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

8 Article Association analyses based on false discovery rate implicate new loci for coronary artery disease. 2017

Nelson, Christopher P / Goel, Anuj / Butterworth, Adam S / Kanoni, Stavroula / Webb, Tom R / Marouli, Eirini / Zeng, Lingyao / Ntalla, Ioanna / Lai, Florence Y / Hopewell, Jemma C / Giannakopoulou, Olga / Jiang, Tao / Hamby, Stephen E / Di Angelantonio, Emanuele / Assimes, Themistocles L / Bottinger, Erwin P / Chambers, John C / Clarke, Robert / Palmer, Colin N A / Cubbon, Richard M / Ellinor, Patrick / Ermel, Raili / Evangelou, Evangelos / Franks, Paul W / Grace, Christopher / Gu, Dongfeng / Hingorani, Aroon D / Howson, Joanna M M / Ingelsson, Erik / Kastrati, Adnan / Kessler, Thorsten / Kyriakou, Theodosios / Lehtimäki, Terho / Lu, Xiangfeng / Lu, Yingchang / März, Winfried / McPherson, Ruth / Metspalu, Andres / Pujades-Rodriguez, Mar / Ruusalepp, Arno / Schadt, Eric E / Schmidt, Amand F / Sweeting, Michael J / Zalloua, Pierre A / AlGhalayini, Kamal / Keavney, Bernard D / Kooner, Jaspal S / Loos, Ruth J F / Patel, Riyaz S / Rutter, Martin K / Tomaszewski, Maciej / Tzoulaki, Ioanna / Zeggini, Eleftheria / Erdmann, Jeanette / Dedoussis, George / Björkegren, Johan L M / Anonymous3681104 / Anonymous3691104 / Anonymous3701104 / Schunkert, Heribert / Farrall, Martin / Danesh, John / Samani, Nilesh J / Watkins, Hugh / Deloukas, Panos. ·Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK. · Centre for Genomic Health, Queen Mary University of London, London, UK. · German Heart Center Munich, Clinic at Technische Universität München and Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, Munich, Germany. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK. · Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK. · Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK. · Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA. · Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia. · Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. · Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden. · Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA. · Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Institute of Cardiovascular Science, University College London,London, UK. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA. · Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. · Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. · Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany. · Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK. · Clinical Gene Networks AB, Stockholm, Sweden. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. · Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. · Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. · Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Farr Institute of Health Informatics, UCL, London, UK. · Bart's Heart Centre, St Bartholomew's Hospital, London, UK. · Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. · Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Wellcome Trust Sanger Institute, Hinxton, UK. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · University Heart Center Lübeck, Lübeck, Germany. · Department of Nutrition-Dietetics, Harokopio University, Athens, Greece. · Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #28714975.

ABSTRACT: Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10

9 Article Functional Characterization of the 2017

Kessler, Thorsten / Wobst, Jana / Wolf, Bernhard / Eckhold, Juliane / Vilne, Baiba / Hollstein, Ronja / von Ameln, Simon / Dang, Tan An / Sager, Hendrik B / Moritz Rumpf, Philipp / Aherrahrou, Redouane / Kastrati, Adnan / Björkegren, Johan L M / Erdmann, Jeanette / Lusis, Aldons J / Civelek, Mete / Kaiser, Frank J / Schunkert, Heribert. ·From Deutsches Herzzentrum München, Klinik für Herz-und Kreislauferkrankungen, Technische Universität München, Munich, Germany (T.K., J.W., B.W., B.V., S.V.A., T.A.D., H.B.S., P.M.R., A.K., H.S.) · Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Germany (J. Eckhold, R.H., F.J.K.) · Center for Public Health Genomics, Department of Biomedical Engineering, University of Virginia, Charlottesville (R.A., M.C.) · DZHK e.V. (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (A.K., H.S.) · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (J.L.M.B.) · Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia (J.L.M.B.) · Institut für Integrative und Experimentelle Genomik and Universitäres Herzzentrum Lübeck, Universität zu Lübeck, Germany (J. Erdmann) · DZHK e.V. (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany (J. Erdmann, F.J.K.) · and Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles (A.J.L., M.C.). ·Circulation · Pubmed #28487391.

ABSTRACT: BACKGROUND: A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses METHODS: Gene expression and protein expression were analyzed with quantitative polymerase chain reaction and immunoblotting, respectively. Putative allele-specific transcription factors were identified with in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed with reporter gene assays. To assess the effect of zinc finger E box-binding homeobox 1 transcription factor (ZEB1), siRNA-mediated knockdown and overexpression experiments were performed. Association of RESULTS: Whole-blood CONCLUSIONS: Rs7692387 is located in an intronic site that modulates

10 Article Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease. 2017

Webb, Thomas R / Erdmann, Jeanette / Stirrups, Kathleen E / Stitziel, Nathan O / Masca, Nicholas G D / Jansen, Henning / Kanoni, Stavroula / Nelson, Christopher P / Ferrario, Paola G / König, Inke R / Eicher, John D / Johnson, Andrew D / Hamby, Stephen E / Betsholtz, Christer / Ruusalepp, Arno / Franzén, Oscar / Schadt, Eric E / Björkegren, Johan L M / Weeke, Peter E / Auer, Paul L / Schick, Ursula M / Lu, Yingchang / Zhang, He / Dube, Marie-Pierre / Goel, Anuj / Farrall, Martin / Peloso, Gina M / Won, Hong-Hee / Do, Ron / van Iperen, Erik / Kruppa, Jochen / Mahajan, Anubha / Scott, Robert A / Willenborg, Christina / Braund, Peter S / van Capelleveen, Julian C / Doney, Alex S F / Donnelly, Louise A / Asselta, Rosanna / Merlini, Pier A / Duga, Stefano / Marziliano, Nicola / Denny, Josh C / Shaffer, Christian / El-Mokhtari, Nour Eddine / Franke, Andre / Heilmann, Stefanie / Hengstenberg, Christian / Hoffmann, Per / Holmen, Oddgeir L / Hveem, Kristian / Jansson, Jan-Håkan / Jöckel, Karl-Heinz / Kessler, Thorsten / Kriebel, Jennifer / Laugwitz, Karl L / Marouli, Eirini / Martinelli, Nicola / McCarthy, Mark I / Van Zuydam, Natalie R / Meisinger, Christa / Esko, Tõnu / Mihailov, Evelin / Escher, Stefan A / Alver, Maris / Moebus, Susanne / Morris, Andrew D / Virtamo, Jarma / Nikpay, Majid / Olivieri, Oliviero / Provost, Sylvie / AlQarawi, Alaa / Robertson, Neil R / Akinsansya, Karen O / Reilly, Dermot F / Vogt, Thomas F / Yin, Wu / Asselbergs, Folkert W / Kooperberg, Charles / Jackson, Rebecca D / Stahl, Eli / Müller-Nurasyid, Martina / Strauch, Konstantin / Varga, Tibor V / Waldenberger, Melanie / Anonymous491201 / Zeng, Lingyao / Chowdhury, Rajiv / Salomaa, Veikko / Ford, Ian / Jukema, J Wouter / Amouyel, Philippe / Kontto, Jukka / Anonymous501201 / Nordestgaard, Børge G / Ferrières, Jean / Saleheen, Danish / Sattar, Naveed / Surendran, Praveen / Wagner, Aline / Young, Robin / Howson, Joanna M M / Butterworth, Adam S / Danesh, John / Ardissino, Diego / Bottinger, Erwin P / Erbel, Raimund / Franks, Paul W / Girelli, Domenico / Hall, Alistair S / Hovingh, G Kees / Kastrati, Adnan / Lieb, Wolfgang / Meitinger, Thomas / Kraus, William E / Shah, Svati H / McPherson, Ruth / Orho-Melander, Marju / Melander, Olle / Metspalu, Andres / Palmer, Colin N A / Peters, Annette / Rader, Daniel J / Reilly, Muredach P / Loos, Ruth J F / Reiner, Alex P / Roden, Dan M / Tardif, Jean-Claude / Thompson, John R / Wareham, Nicholas J / Watkins, Hugh / Willer, Cristen J / Samani, Nilesh J / Schunkert, Heribert / Deloukas, Panos / Kathiresan, Sekar / Anonymous511201. ·Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom. · Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri. · Deutsches Herzzentrum München, Technische Universität München, München, Germany; DZHK, Partner Site Munich Heart Alliance, Munich, Germany. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts. · Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden. · Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · School of Public Heath, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin. · Fred Hutchinson Cancer Research Center, Seattle, Washington; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan. · Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands. · Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. · Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom. · Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy. · Niguarda Hospital, Milan, Italy. · Azienda Sanitaria Locale 3 San Francesco, Nuoro, Italy 3, Nuoro, Italy. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical informatics, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. · Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri; Deutsches Herzzentrum München, Technische Universität München, München, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway. · Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Sweden. · Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany. · Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. · Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road Headington, Oxford, Oxford, United Kingdom. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia. · School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, Scotland, United Kingdom. · National Institute for Health and Welfare (THL), Helsinki, Finland. · Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Montreal Heart Institute, Montreal, Quebec, Canada. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom. · Merck Sharp & Dohme, Rahway, New Jersey. · Department of Cardiology, Division Heart & Lungs, UMC Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom. · Fred Hutchinson Cancer Research Center, Seattle, Washington. · Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Ohio State University, Columbus, Ohio. · Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. · Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom. · Department of Cardiology, Leiden University Medical Center, Leiden and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France. · Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Toulouse University School of Medicine, Toulouse, France. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Noncommunicable Diseases, Karachi, Pakistan. · British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. · Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. · Department of Epîdemiology and Public Health, University of Strasbourg, Strasbourg, France. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. · Parma University Hospital, Parma, Italy. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York. · Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom. · Deutsches Herzzentrum München, Technische Universität München, München, Germany. · Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University Kiel, Kiel, Germany. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany. · Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina. · Department of Clinical Sciences in Malmo, Lund University, Clinical Research Center, Malmo, Sweden. · Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden. · DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Department of Genetics, Cardiovascular Institute and Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Division of Cardiology, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York. · Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom. · Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan. · Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address: njs@le.ac.uk. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: p.deloukas@qmul.ac.uk. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts. ·J Am Coll Cardiol · Pubmed #28209224.

ABSTRACT: BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

11 Article Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. 2016

Mäkikallio, Timo / Holm, Niels R / Lindsay, Mitchell / Spence, Mark S / Erglis, Andrejs / Menown, Ian B A / Trovik, Thor / Eskola, Markku / Romppanen, Hannu / Kellerth, Thomas / Ravkilde, Jan / Jensen, Lisette O / Kalinauskas, Gintaras / Linder, Rikard B A / Pentikainen, Markku / Hervold, Anders / Banning, Adrian / Zaman, Azfar / Cotton, Jamen / Eriksen, Erlend / Margus, Sulev / Sørensen, Henrik T / Nielsen, Per H / Niemelä, Matti / Kervinen, Kari / Lassen, Jens F / Maeng, Michael / Oldroyd, Keith / Berg, Geoff / Walsh, Simon J / Hanratty, Colm G / Kumsars, Indulis / Stradins, Peteris / Steigen, Terje K / Fröbert, Ole / Graham, Alastair N J / Endresen, Petter C / Corbascio, Matthias / Kajander, Olli / Trivedi, Uday / Hartikainen, Juha / Anttila, Vesa / Hildick-Smith, David / Thuesen, Leif / Christiansen, Evald H / Anonymous4930886. ·Department of Cardiology, Oulu University Hospital, Oulu, Finland. · Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark. · Department of Cardiology, Golden Jubilee National Hospital, Clydebank, Scotland. · Belfast Heart Centre, Belfast Trust, Belfast, Northern Ireland. · Latvia Centre of Cardiology, Paul Stradins Clinical Hospital, Riga, Latvia. · Craigavon Cardiac Centre, Craigavon, Northern Ireland. · Department of Cardiology, University of Northern Norway, Tromsø, Norway. · Heart Hospital, Tampere University Hospital, Tampere, Finland. · Heart Center, Kuopio University Hospital, Kuopio, Finland. · Department of Cardiology, Örebro University Hospital, Örebro, Sweden. · Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark. · Department of Cardiology, Odense University Hospital, Odense, Denmark. · Department of Cardiology, Vilnius University Hospital, Vilnius, Lithuania. · Department of Cardiology, Danderyd Hospital, Stockholm, Sweden. · Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland. · Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · Oxford Heart Centre, Oxford, UK. · Department of Cardiology, Freeman Hospital and Institute of Cellular Medicine, Newcastle, UK. · Heart and Lung Centre, New Cross Hospital, Wolverhampton, UK. · Department of Cardiology, Haukeland University Hospital, Bergen, Norway. · Department of Cardiology, East Tallinn Hospital, Tallinn, Estonia. · Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; Department of Health Research and Policy (Epidemiology), Stanford University, Stanford, CA, USA. · Department of Cardiac Surgery, Aarhus University Hospital, Skejby, Aarhus, Denmark. · Department of Cardiovascular Surgery, University of Northern Norway, Tromsø, Norway. · Department of Cardiology, Karolinska University Hospital, Huddinge, Stockholm, Sweden. · Sussex Cardiac Centre, Brighton and Sussex University Hospital, Brighton, UK. · Department of Cardiac Surgery, Oulu University Hospital, Finland. · Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark. Electronic address: evald.christiansen@dadlnet.dk. ·Lancet · Pubmed #27810312.

ABSTRACT: BACKGROUND: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. METHODS: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. FINDINGS: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke. INTERPRETATION: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. FUNDING: Biosensors, Aarhus University Hospital, and participating sites.

12 Article Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting. 2016

Lamy, André / Devereaux, P J / Prabhakaran, Dorairaj / Taggart, David P / Hu, Shengshou / Straka, Zbynek / Piegas, Leopoldo S / Avezum, Alvaro / Akar, Ahmet R / Lanas Zanetti, Fernando / Jain, Anil R / Noiseux, Nicolas / Padmanabhan, Chandrasekar / Bahamondes, Juan-Carlos / Novick, Richard J / Tao, Liang / Olavegogeascoechea, Pablo A / Airan, Balram / Sulling, Toomas-Andres / Whitlock, Richard P / Ou, Yongning / Gao, Peggy / Pettit, Shirley / Yusuf, Salim / Anonymous5090885. ·From the Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, ON (A.L., P.J.D., R.P.W., Y.O., P.G., S.P., S.Y.), Centre Hospitalier de l'Université de Montréal, Montreal (N.N.), and the University of Calgary, Calgary, AB (R.J.N.) - all in Canada · the Center for Chronic Disease Control, Gurgaon (D.P.), SAL Hospital, Ahmedabad (A.R.J.), G. Kuppuswamy Naidu Memorial Hospital, Coimbatore (C.P.), and All India Institute of Medical Sciences, New Delhi (B.A.) - all in India · the University of Oxford, Oxford, United Kingdom (D.P.T.) · Fu Wai Cardiovascular Hospital, Xicheng District, Beijing (S.H.), and Wuhan Asia Heart Hospital, Wuhan (L.T.) - both in China · Third Faculty of Medicine Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic (Z.S.) · Instituto Dante Pazzanese de Cardiologia, São Paulo (L.S.P., A.A.) · Ankara University School of Medicine, Ankara, Turkey (A.R.A.) · Hospital Regional de Temuco and Universidad de la Frontera, Temuco, Chile (F.L.Z., J.-C.B.) · Fundación Médica de Río Negro y Neuquén, Rio Negro, Argentina (P.A.O.) · and North Estonia Medical Center, Tallinn, Estonia (T.-A.S.). ·N Engl J Med · Pubmed #27771985.

ABSTRACT: BACKGROUND: We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). METHODS: A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. RESULTS: There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and $14,992, respectively; between-group difference, $115; 95% CI, -$697 to $927). There were no significant between-group differences in quality-of-life measures. CONCLUSIONS: In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .).

13 Article No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis. 2016

Loley, Christina / Alver, Maris / Assimes, Themistocles L / Bjonnes, Andrew / Goel, Anuj / Gustafsson, Stefan / Hernesniemi, Jussi / Hopewell, Jemma C / Kanoni, Stavroula / Kleber, Marcus E / Lau, King Wai / Lu, Yingchang / Lyytikäinen, Leo-Pekka / Nelson, Christopher P / Nikpay, Majid / Qu, Liming / Salfati, Elias / Scholz, Markus / Tukiainen, Taru / Willenborg, Christina / Won, Hong-Hee / Zeng, Lingyao / Zhang, Weihua / Anand, Sonia S / Beutner, Frank / Bottinger, Erwin P / Clarke, Robert / Dedoussis, George / Do, Ron / Esko, Tõnu / Eskola, Markku / Farrall, Martin / Gauguier, Dominique / Giedraitis, Vilmantas / Granger, Christopher B / Hall, Alistair S / Hamsten, Anders / Hazen, Stanley L / Huang, Jie / Kähönen, Mika / Kyriakou, Theodosios / Laaksonen, Reijo / Lind, Lars / Lindgren, Cecilia / Magnusson, Patrik K E / Marouli, Eirini / Mihailov, Evelin / Morris, Andrew P / Nikus, Kjell / Pedersen, Nancy / Rallidis, Loukianos / Salomaa, Veikko / Shah, Svati H / Stewart, Alexandre F R / Thompson, John R / Zalloua, Pierre A / Chambers, John C / Collins, Rory / Ingelsson, Erik / Iribarren, Carlos / Karhunen, Pekka J / Kooner, Jaspal S / Lehtimäki, Terho / Loos, Ruth J F / März, Winfried / McPherson, Ruth / Metspalu, Andres / Reilly, Muredach P / Ripatti, Samuli / Sanghera, Dharambir K / Thiery, Joachim / Watkins, Hugh / Deloukas, Panos / Kathiresan, Sekar / Samani, Nilesh J / Schunkert, Heribert / Erdmann, Jeanette / König, Inke R. ·Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Hamburg-Lübeck-Kiel, Lübeck, Germany. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, Tartu, Estonia. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine Stanford, Standford, California, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. · Department of Cardiology, Heart Hospital and University of Tampere School of Medicine, Tampere, Finland. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. · The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, USA. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. · Ruddy Canadian Cardiovascular Genetics Centre University of Ottawa Heart Institute, Ottawa, Canada. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute for Medical Informatics, Statistics and Epidemiology/Medical Faculty/University of Leipzig, Leipzig, Germany. · LIFE Research Center of Civilization Diseases, Leipzig, Germany. · Analytic and Translation Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany and University Heart Center Luebeck, Campus Lübeck, Lübeck, Germany. · Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Korea. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. · Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. · Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany. · Harokopio University Athens, Athens, Greece. · The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, USA. · The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA. · The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France. · Department of Public Health and Caring Sciences, Geriatrics, Uppsala Universit, Uppsala, Sweden. · Duke University School of Medicine, Durham, North Carolina, USA. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, UK. · Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. · Cleveland Clinic, Cleveland, Ohio, USA. · Boston VA Research Institute, Inc., Boston, Massachusetts, USA. · Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. · Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland. · Zora Biosciences, Espoo, Finland. · Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. · Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Second Department of Cardiology, University General Hospital Attikon, Athens, Greece. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · Department of Health Sciences, University of Leicester, Leicester, UK. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Harvard School of Public Health, Boston, Massachusetts, USA. · Imperial College Healthcare NHS Trust, London, UK. · Kaiser Permanente, Division of Research, Oakland, California, USA. · Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, USA. · Synlab Academy, Synlab Services GmbH, Mannheim, Germany. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Hjelt Institute, University of Helsinki, Helsinki, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. · Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA. · Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Sci Rep · Pubmed #27731410.

ABSTRACT: In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

14 Article Genome-wide associations for birth weight and correlations with adult disease. 2016

Horikoshi, Momoko / Beaumont, Robin N / Day, Felix R / Warrington, Nicole M / Kooijman, Marjolein N / Fernandez-Tajes, Juan / Feenstra, Bjarke / van Zuydam, Natalie R / Gaulton, Kyle J / Grarup, Niels / Bradfield, Jonathan P / Strachan, David P / Li-Gao, Ruifang / Ahluwalia, Tarunveer S / Kreiner, Eskil / Rueedi, Rico / Lyytikäinen, Leo-Pekka / Cousminer, Diana L / Wu, Ying / Thiering, Elisabeth / Wang, Carol A / Have, Christian T / Hottenga, Jouke-Jan / Vilor-Tejedor, Natalia / Joshi, Peter K / Boh, Eileen Tai Hui / Ntalla, Ioanna / Pitkänen, Niina / Mahajan, Anubha / van Leeuwen, Elisabeth M / Joro, Raimo / Lagou, Vasiliki / Nodzenski, Michael / Diver, Louise A / Zondervan, Krina T / Bustamante, Mariona / Marques-Vidal, Pedro / Mercader, Josep M / Bennett, Amanda J / Rahmioglu, Nilufer / Nyholt, Dale R / Ma, Ronald Ching Wan / Tam, Claudia Ha Ting / Tam, Wing Hung / Anonymous24350882 / Ganesh, Santhi K / van Rooij, Frank Ja / Jones, Samuel E / Loh, Po-Ru / Ruth, Katherine S / Tuke, Marcus A / Tyrrell, Jessica / Wood, Andrew R / Yaghootkar, Hanieh / Scholtens, Denise M / Paternoster, Lavinia / Prokopenko, Inga / Kovacs, Peter / Atalay, Mustafa / Willems, Sara M / Panoutsopoulou, Kalliope / Wang, Xu / Carstensen, Lisbeth / Geller, Frank / Schraut, Katharina E / Murcia, Mario / van Beijsterveldt, Catharina Em / Willemsen, Gonneke / Appel, Emil V R / Fonvig, Cilius E / Trier, Caecilie / Tiesler, Carla Mt / Standl, Marie / Kutalik, Zoltán / Bonas-Guarch, Sílvia / Hougaard, David M / Sánchez, Friman / Torrents, David / Waage, Johannes / Hollegaard, Mads V / de Haan, Hugoline G / Rosendaal, Frits R / Medina-Gomez, Carolina / Ring, Susan M / Hemani, Gibran / McMahon, George / Robertson, Neil R / Groves, Christopher J / Langenberg, Claudia / Luan, Jian'an / Scott, Robert A / Zhao, Jing Hua / Mentch, Frank D / MacKenzie, Scott M / Reynolds, Rebecca M / Anonymous24360882 / Lowe, William L / Tönjes, Anke / Stumvoll, Michael / Lindi, Virpi / Lakka, Timo A / van Duijn, Cornelia M / Kiess, Wieland / Körner, Antje / Sørensen, Thorkild Ia / Niinikoski, Harri / Pahkala, Katja / Raitakari, Olli T / Zeggini, Eleftheria / Dedoussis, George V / Teo, Yik-Ying / Saw, Seang-Mei / Melbye, Mads / Campbell, Harry / Wilson, James F / Vrijheid, Martine / de Geus, Eco Jcn / Boomsma, Dorret I / Kadarmideen, Haja N / Holm, Jens-Christian / Hansen, Torben / Sebert, Sylvain / Hattersley, Andrew T / Beilin, Lawrence J / Newnham, John P / Pennell, Craig E / Heinrich, Joachim / Adair, Linda S / Borja, Judith B / Mohlke, Karen L / Eriksson, Johan G / Widén, Elisabeth E / Kähönen, Mika / Viikari, Jorma S / Lehtimäki, Terho / Vollenweider, Peter / Bønnelykke, Klaus / Bisgaard, Hans / Mook-Kanamori, Dennis O / Hofman, Albert / Rivadeneira, Fernando / Uitterlinden, André G / Pisinger, Charlotta / Pedersen, Oluf / Power, Christine / Hyppönen, Elina / Wareham, Nicholas J / Hakonarson, Hakon / Davies, Eleanor / Walker, Brian R / Jaddoe, Vincent Wv / Jarvelin, Marjo-Riitta / Grant, Struan Fa / Vaag, Allan A / Lawlor, Debbie A / Frayling, Timothy M / Davey Smith, George / Morris, Andrew P / Ong, Ken K / Felix, Janine F / Timpson, Nicholas J / Perry, John Rb / Evans, David M / McCarthy, Mark I / Freathy, Rachel M. ·Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. · Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK. · MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK. · The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. · School of Women's and Infants' Health, The University of Western Australia, Perth, Australia. · The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. · Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, the Netherlands. · Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark. · Department of Pediatrics, University of California San Diego, La Jolla, California, USA. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. · Population Health Research Institute, St George's University of London, London, Cranmer Terrace, UK. · Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. · COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. · Steno Diabetes Center, Gentofte, Denmark. · Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. · Swiss Institute of Bioinformatics, Lausanne, Switzerland. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. · Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland. · Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. · Institute of Epidemiology I, Helmholtz Zentrum München- German Research Center for Environmental Health, Neuherberg, Germany. · Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany. · Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, the Netherlands. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. · Universitat Pompeu Fabra (UPF), Barcelona, Spain. · CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. · Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK. · Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore. · William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. · Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. · Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland. · KUL - University of Leuven, Department of Neurosciences, Leuven, Belgium. · Translational Immunology Laboratory, VIB, Leuven, Belgium. · Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, USA. · Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK. · Center for Genomic Regulation (CRG), Barcelona, Spain. · Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland. · Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain. · Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia. · Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China. · Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China. · Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China. · Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China. · Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. · European Centre for Environment and Human Health, University of Exeter, Truro, UK. · Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK. · School of Social and Community Medicine, University of Bristol, Bristol, UK. · Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. · IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany. · Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. · FISABIO-Universitat Jaume I-Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain. · The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark. · Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland. · Danish Center for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark. · Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark. · Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain. · Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. · Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands. · BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, Scotland, UK. · Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, USA. · Medical Department, University of Leipzig, Leipzig, Germany. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Pediatric Research Center, Department of Women´s & Child Health, University of Leipzig, Leipzig, Germany. · Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark. · Department of Pediatrics, Turku University Hospital, Turku, Finland. · Department of Physiology, University of Turku, Turku, Finland. · Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, Turku, Finland. · Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. · Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore. · Life Sciences Institute, National University of Singapore, Singapore, Singapore. · Singapore Eye Research Institute, Singapore, Singapore. · Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark. · Department of Medicine, Stanford School of Medicine, Stanford, California, USA. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK. · EMGO Institute for Health and Care Research, VU University and VU University Medical Center, Amsterdam, the Netherlands. · Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland. · Biocenter Oulu, University of Oulu, Finland. · School of Medicine and Pharmacology, Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia. · Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany. · Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA. · USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines. · Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines. · National Institute for Health and Welfare, Helsinki, Finland. · Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. · Folkhälsan Research Center, Helsinki, Finland. · Department of Clinical Physiology, Tampere University Hopital, Tampere, Finland. · Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland. · Division of Medicine, Turku University Hospital, Turku, Finland. · Department of Medicine, University of Turku, Turku, Finland. · Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands. · Epidemiology Section, BESC Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. · Research Center for Prevention and Health Capital Region, Center for Sundhed, Rigshospitalet - Glostrup, Copenhagen University, Glostrup, Denmark. · Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UK. · Centre for Population Health Research, School of Health Sciences, and Sansom Institute, University of South Australia, Adelaide, Australia. · South Australian Health and Medical Research Institute, Adelaide, Australia. · Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK. · Unit of Primary Care, Oulu University Hospital, Oulu, Finland. · Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. · Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Department of Paediatrics, University of Cambridge, Cambridge, UK. · Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK. ·Nature · Pubmed #27680694.

ABSTRACT: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10

15 Article Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. 2016

Franzén, Oscar / Ermel, Raili / Cohain, Ariella / Akers, Nicholas K / Di Narzo, Antonio / Talukdar, Husain A / Foroughi-Asl, Hassan / Giambartolomei, Claudia / Fullard, John F / Sukhavasi, Katyayani / Köks, Sulev / Gan, Li-Ming / Giannarelli, Chiara / Kovacic, Jason C / Betsholtz, Christer / Losic, Bojan / Michoel, Tom / Hao, Ke / Roussos, Panos / Skogsberg, Josefin / Ruusalepp, Arno / Schadt, Eric E / Björkegren, Johan L M. ·Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. · Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia. · Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. · Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden. · Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. · Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. · Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden. · Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. · Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. · AstraZeneca-Karolinska Integrated CardioMetabolic Centre (ICMC), Karolinska Institutet, Novum, Blickagången 6, 141 57 Huddinge, Sweden. Department of Immunology, Genetics and Pathology Dag Hammarskjölds Väg 20, 751 85 Uppsala, Sweden. · Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Old College, South Bridge, Edinburgh EH8 9YL, UK. · Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Department of Psychiatry, J. J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), 130 West Kingsbridge Road, Bronx, NY 10468, USA. · Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia. · Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden. johan.bjorkegren@mssm.edu. ·Science · Pubmed #27540175.

ABSTRACT: Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.

16 Article Early Biomarkers of Renal Damage in Relation to Arterial Stiffness and Inflammation in Male Coronary Artery Disease Patients. 2016

Paapstel, Kaido / Zilmer, Mihkel / Eha, Jaan / Tootsi, Kaspar / Piir, Anneli / Kals, Jaak. ·Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia. ·Kidney Blood Press Res · Pubmed #27433796.

ABSTRACT: BACKGROUND/AIMS: Plasma neutrophil gelatinase-associated lipocalin (NGAL), urinary liver-type fatty acid-binding protein (L-FABP) and urinary kidney injury molecule-1 (KIM-1) have emerged as promising biomarkers for both acute and chronic kidney injury that also provide prognostic value for cardiovascular morbidity and mortality. Our aim was to evaluate their relationships with arterial stiffness and inflammation in coronary artery disease (CAD) patients and in clinically healthy controls. METHODS: We studied 52 patients with CAD (age 63.2 ± 9.2 years) and 41 healthy controls (age 60.1 ± 7.2 years). Urinary L-FABP and KIM-1 as well as serum NGAL, adiponectin and resistin levels were measured using the enzyme-linked immunosorbent assay method. The technique of applanation tonometry was used for non-invasive pulse wave analysis and pulse wave velocity assessments. RESULTS: Urinary L-FABP and KIM-1 were independent determinants of cf-PWV for the CAD patients (R2=0.584, P<0.001) but not for the controls. Adiponectin correlated with log-KIM-1 (r=0.31, P=0.028) only for the patients, while NGAL correlated with WBC count (rho=0.29, P=0.038; r=0.35, P=0.029) and resistin (rho=0.60, P<0.001; r=0.57, P<0.001) for both the CAD and control groups, respectively. CONCLUSION: Our findings suggest that urinary L-FABP and KIM-1 may be independently associated with aortic stiffness in individuals with CAD.

17 Article Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci. 2016

Miller, Clint L / Pjanic, Milos / Wang, Ting / Nguyen, Trieu / Cohain, Ariella / Lee, Jonathan D / Perisic, Ljubica / Hedin, Ulf / Kundu, Ramendra K / Majmudar, Deshna / Kim, Juyong B / Wang, Oliver / Betsholtz, Christer / Ruusalepp, Arno / Franzén, Oscar / Assimes, Themistocles L / Montgomery, Stephen B / Schadt, Eric E / Björkegren, Johan L M / Quertermous, Thomas. ·Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden. · Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 05, Sweden. · Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm SE-171 77, Sweden. · Department of Cardiac Surgery, Tartu University Hospital, Tartu 50406, Estonia. · Clinical Gene Networks AB, Stockholm SE-114 44, Sweden. · Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu 50406, Estonia. ·Nat Commun · Pubmed #27386823.

ABSTRACT: Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.

18 Article Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease. 2016

Talukdar, Husain A / Foroughi Asl, Hassan / Jain, Rajeev K / Ermel, Raili / Ruusalepp, Arno / Franzén, Oscar / Kidd, Brian A / Readhead, Ben / Giannarelli, Chiara / Kovacic, Jason C / Ivert, Torbjörn / Dudley, Joel T / Civelek, Mete / Lusis, Aldons J / Schadt, Eric E / Skogsberg, Josefin / Michoel, Tom / Björkegren, Johan L M. ·Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, 51014 Tartu, Estonia. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, 51014 Tartu, Estonia; Clinical Gene Networks AB, 114 44 Stockholm, Sweden. · Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. · Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Thoracic Surgery, Karolinska University Hospital, 171 76 Stockholm, Sweden. · Departments of Medicine, Cardiology, Human Genetics, Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90024, USA. · Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK. · Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, 51014 Tartu, Estonia; Clinical Gene Networks AB, 114 44 Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: johan.bjorkegren@mssm.edu. ·Cell Syst · Pubmed #27135365.

ABSTRACT: Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.

19 Article Do Stroke Patients Know Their Risk Factors? 2016

Soomann, Maarja / Vibo, Riina / Kõrv, Janika. ·Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia. Electronic address: maarja.soomann@gmail.com. · Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia. ·J Stroke Cerebrovasc Dis · Pubmed #26654663.

ABSTRACT: BACKGROUND: Risk factor management is the key to stroke prevention. Although several studies have assessed the awareness of different risk factors in the general public, there are limited data available on how well acute stroke patients know their own risk factors. The aim of this study was to assess stroke patients' informedness of their own stroke risk factors. METHODS: All consecutive eligible acute stroke and transient ischemic attack patients hospitalized at the Tartu University Hospital, Department of Neurology, during 9 months in 2010 were interviewed about different stroke risk factors within 72 hours from hospitalization. The respective information was also retrieved from medical records. RESULTS: Of the 341 patients admitted during the study period, 195 were eligible for the interview. Diabetes was the best known risk factor (89%) followed by hypertension (80%), atrial fibrillation (78%), previous stroke (77%), and heart failure and/or ischemic heart disease (66%). CONCLUSIONS: We found that acute stroke patients are best informed of their diabetes and worst informed of their ischemic heart disease and/or heart failure. There is, however, room for amelioration in the awareness of all of the studied risk factors. More attention should be addressed to explaining the risks and treatment options to patients at risk of stroke and the general population.

20 Article Association Between Fibulin-1 and Aortic Augmentation Index in Male Patients with Peripheral Arterial Disease. 2016

Paapstel, K / Zilmer, M / Eha, J / Tootsi, K / Piir, A / Kals, J. ·Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia; Endothelial Centre, University of Tartu, Tartu, Estonia. Electronic address: paapstel@outlook.com. · Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia; Endothelial Centre, University of Tartu, Tartu, Estonia. · Endothelial Centre, University of Tartu, Tartu, Estonia; Department of Cardiology, University of Tartu, Tartu, Estonia. · Endothelial Centre, University of Tartu, Tartu, Estonia. · Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia. · Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia; Endothelial Centre, University of Tartu, Tartu, Estonia; Department of Vascular Surgery, Tartu University Hospital, Tartu, Estonia. ·Eur J Vasc Endovasc Surg · Pubmed #26507503.

ABSTRACT: BACKGROUND: Fibulin-1 (FBLN-1), a newly identified biomarker for vascular stiffness in type 2 diabetes, may participate in the pathophysiological processes leading to progression of arterial stiffness in atherosclerosis. In the present study, the relationship between FBLN-1 and arterial stiffness was examined in patients with atherosclerosis and in healthy subjects. METHODS: Thirty-eight patients with peripheral arterial disease (PAD) (age 62.4 ± 9.0 years), 38 patients with coronary artery disease (CAD) (age 64.0 ± 9.5 years), and 30 apparently healthy controls (age 61.1 ± 6.4 years) were studied. Serum FBLN-1, oxidized low density lipoprotein (oxLDL), resistin and plasminogen activator inhibitor-1 (PAI-1) levels were measured using the enzyme linked immunosorbent assay method. The technique of applanation tonometry was used for non-invasive pulse wave analysis and pulse wave velocity assessments. RESULTS: The levels of FBLN-1 (PAD = 9.4 [4.9-17.8] vs. CAD = 7.1 [4.8-11.8] vs. controls = 5.6 [4.1-8.4] μg/mL; p = .005), carotid-femoral pulse wave velocity (cf-PWV) (9.8 ± 2.2 vs. 9.5 ± 2.2 vs. 8.3 ± 2.2 m/s; p = .023) and the heart rate corrected augmentation index (AIx@75) (29.4 ± 7.2 vs. 19.2 ± 7.2 vs. 15.4 ± 7.1%; p < .001), differed among the three groups. A correlation between FBLN-1 and AIx@75 was observed only in patients with PAD (rho = 0.37, p = .021). The relationship retained statistical significance in a multiple regression model after adjustment for potential confounders. CONCLUSIONS: An independent association was demonstrated between serum FBLN-1 and AIx@75 in the PAD group. Thus, the findings suggest that FBLN-1 may play a role in arterial stiffening in patients with atherosclerosis.

21 Article Exposure to sixty minutes of hyperoxia upregulates myocardial humanins in patients with coronary artery disease - a pilot study. 2015

Karu, I / Tahepold, P / Ruusalepp, A / Reimann, E / Koks, S / Starkopf, J. ·Clinic of Anesthesiology and Intensive Care, North Estonia Medical Centre, Tallinn, Estonia. inga.karu@regionaalhaigla.ee. · Department of Anaesthesiology and Intensive Care, University of Tartu, Tartu, Estonia. · Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia. · Department of Pathophysiology, University of Tartu, Tartu, Estonia. ·J Physiol Pharmacol · Pubmed #26769839.

ABSTRACT: In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduced and different intracellular protective mechanisms and their effects have been described. To study whether similar protective phenotype can be induced by hyperoxia also in humans, gene expression profile after hyperoxic exposure was analyzed. Adult patients were randomized to be ventilated with either FiO2 0.4 (n = 14) or 1.0 (n = 10) for 60 minutes before coronary artery bypass grafting. A tissue sample from the right atrial appendage was taken for gene analysis and expression profile analysis on genome wide level by RNA-seq analysis was applied. Exposure to > 96% oxygen for 60 minutes significantly changed the expression of 20 different genes, including upregulation of two different humanins - MTRNR2L2 and MTRNR2L8, and activated a "cell survival" network as detected by Ingenuity Pathway Analyses. We concluded that administration of > 96% oxygen for 1 hour changes gene expression in the myocardium of the patients with coronary artery disease and may enhance cell survival capability.

22 Article A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. 2015

Nikpay, Majid / Goel, Anuj / Won, Hong-Hee / Hall, Leanne M / Willenborg, Christina / Kanoni, Stavroula / Saleheen, Danish / Kyriakou, Theodosios / Nelson, Christopher P / Hopewell, Jemma C / Webb, Thomas R / Zeng, Lingyao / Dehghan, Abbas / Alver, Maris / Armasu, Sebastian M / Auro, Kirsi / Bjonnes, Andrew / Chasman, Daniel I / Chen, Shufeng / Ford, Ian / Franceschini, Nora / Gieger, Christian / Grace, Christopher / Gustafsson, Stefan / Huang, Jie / Hwang, Shih-Jen / Kim, Yun Kyoung / Kleber, Marcus E / Lau, King Wai / Lu, Xiangfeng / Lu, Yingchang / Lyytikäinen, Leo-Pekka / Mihailov, Evelin / Morrison, Alanna C / Pervjakova, Natalia / Qu, Liming / Rose, Lynda M / Salfati, Elias / Saxena, Richa / Scholz, Markus / Smith, Albert V / Tikkanen, Emmi / Uitterlinden, Andre / Yang, Xueli / Zhang, Weihua / Zhao, Wei / de Andrade, Mariza / de Vries, Paul S / van Zuydam, Natalie R / Anand, Sonia S / Bertram, Lars / Beutner, Frank / Dedoussis, George / Frossard, Philippe / Gauguier, Dominique / Goodall, Alison H / Gottesman, Omri / Haber, Marc / Han, Bok-Ghee / Huang, Jianfeng / Jalilzadeh, Shapour / Kessler, Thorsten / König, Inke R / Lannfelt, Lars / Lieb, Wolfgang / Lind, Lars / Lindgren, Cecilia M / Lokki, Marja-Liisa / Magnusson, Patrik K / Mallick, Nadeem H / Mehra, Narinder / Meitinger, Thomas / Memon, Fazal-Ur-Rehman / Morris, Andrew P / Nieminen, Markku S / Pedersen, Nancy L / Peters, Annette / Rallidis, Loukianos S / Rasheed, Asif / Samuel, Maria / Shah, Svati H / Sinisalo, Juha / Stirrups, Kathleen E / Trompet, Stella / Wang, Laiyuan / Zaman, Khan S / Ardissino, Diego / Boerwinkle, Eric / Borecki, Ingrid B / Bottinger, Erwin P / Buring, Julie E / Chambers, John C / Collins, Rory / Cupples, L Adrienne / Danesh, John / Demuth, Ilja / Elosua, Roberto / Epstein, Stephen E / Esko, Tõnu / Feitosa, Mary F / Franco, Oscar H / Franzosi, Maria Grazia / Granger, Christopher B / Gu, Dongfeng / Gudnason, Vilmundur / Hall, Alistair S / Hamsten, Anders / Harris, Tamara B / Hazen, Stanley L / Hengstenberg, Christian / Hofman, Albert / Ingelsson, Erik / Iribarren, Carlos / Jukema, J Wouter / Karhunen, Pekka J / Kim, Bong-Jo / Kooner, Jaspal S / Kullo, Iftikhar J / Lehtimäki, Terho / Loos, Ruth J F / Melander, Olle / Metspalu, Andres / März, Winfried / Palmer, Colin N / Perola, Markus / Quertermous, Thomas / Rader, Daniel J / Ridker, Paul M / Ripatti, Samuli / Roberts, Robert / Salomaa, Veikko / Sanghera, Dharambir K / Schwartz, Stephen M / Seedorf, Udo / Stewart, Alexandre F / Stott, David J / Thiery, Joachim / Zalloua, Pierre A / O'Donnell, Christopher J / Reilly, Muredach P / Assimes, Themistocles L / Thompson, John R / Erdmann, Jeanette / Clarke, Robert / Watkins, Hugh / Kathiresan, Sekar / McPherson, Ruth / Deloukas, Panos / Schunkert, Heribert / Samani, Nilesh J / Farrall, Martin. ·Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany. · DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Lübeck, Germany. · William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Deutsches Herzzentrum München, Technische Universität München, München, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany. · Department of Epidemiology, Erasmus University Medical center, Rotterdam, The Netherlands. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. · Diabetes & Obesity Research Program, University of Helsinki, Helsinki, Finland. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. · Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. · Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. · National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Korea. · Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. · Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA. · Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany. · LIFE Research Center of Civilization Diseases, Leipzig, Germany. · Icelandic Heart Association, Kopavogur, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Department of Public Health, University of Helsinki, Helsinki, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK. · Medical Research Institute, University of Dundee, Dundee, UK. · Population Health Research Institute, Hamilton Health Sciences, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. · Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany. · Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK. · Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany. · Department of Dietetics-Nutrition, Harokopio University, Athens, Greece. · INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Hypertension Division, Fuwai Hospital, National Center For Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Klinikum rechts der Isar, München, Germany. · Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden. · Institut für Epidemiologie, Christian-Albrechts Universität zu Kiel, Kiel, Germany. · Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. · Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Punjab Institute of Cardiology, Lahore, Pakistan. · All India Institute of Medical Sciences, New Delhi, India. · Institut für Humangenetik, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Human Genetics, Technische Universität München, München, Germany. · Red Crescent Institute of Cardiology, Hyderabad, Pakistan. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine, Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. · Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. · Department of Haematology, University of Cambridge, Cambridge, UK. · Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. · National Human Genome Center at Beijing, Beijing, China. · National Institue of Cardiovascular Diseases, Karachi, Pakistan. · Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. · Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Imperial College Healthcare NHS Trust, London, UK. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The Berlin Aging Study II; Research Group on Geriatrics; Charité - Universitätsmedizin Berlin, Berlin, Germany. · Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Grupo de Epidemiología y Genética Cardiovascular, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. · MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA. · Division of Endocrinology and Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. · Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Cleveland Clinic, Cleveland, Ohio, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA. · Kaiser Permanente Division of Research, Oakland, California, USA. · Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands. · Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. · Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. · The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, University Hospital Malmö, Malmö, Sweden. · Synlab Academy, Synlab Services GmbH, Mannheim, Germany. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA. · Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · University of Ottawa Heart Institute, Ottawa, Canada. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK. · Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany. · Harvard School of Public Health, Boston, Massachusetts, USA. · National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, USA. · Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Health Sciences, University of Leicester, Leicester, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #26343387.

ABSTRACT: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

23 Article Blood lipids among young children in Europe: results from the European IDEFICS study. 2014

De Henauw, S / Michels, N / Vyncke, K / Hebestreit, A / Russo, P / Intemann, T / Peplies, J / Fraterman, A / Eiben, G / de Lorgeril, M / Tornaritis, M / Molnar, D / Veidebaum, T / Ahrens, W / Moreno, L A / Anonymous3000806. ·1] Department of Public Health, Faculty of Medicine and Health Sciences, University Hospital, Ghent University, Ghent, Belgium [2] Department of Health Sciences, Vesalius College, University College Ghent, Ghent, Belgium. · Department of Public Health, Faculty of Medicine and Health Sciences, University Hospital, Ghent University, Ghent, Belgium. · Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany. · Epidemiology and Population Genetics, Institute of Food Sciences, CNR, Avellino, Italy. · MVZ Dortmund Dr Eberhard und Partner, Dortmund, Germany. · Department of Primary Health Care, University of Gothenburg, Gothenburg, Sweden. · TIMC-IMAG, CNRS UMR 5525, Coeur et nutrition, Faculté de Médecine de Grenoble, Grenoble, France. · Research and Education Institute of Child Health, Strovolos, Cyprus. · National Institute of Health Promotion, University of Pécs, Gyermekklinika, Pécs, Hungary. · Department of Chronic Diseases, National Institute for Health Development, Tallinn, Estonia. · 1] Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany [2] Institute of Statistics, Faculty of Mathematics and Computer Science, University Bremen, Bremen, Germany. · GENUD (Growth, Exercise, Nutrition and Development) research group, School of Health Sciences, University of Zaragoza, Zaragoza, Spain. ·Int J Obes (Lond) · Pubmed #25219412.

ABSTRACT: BACKGROUND: Measurement of cholesterol and triglyceride (TG) fractions in blood has become standard practice in the early detection of atherosclerotic disease pathways. Considerable attention is given nowadays to the presence of these risk factors in children and to start preventive campaigns early in life. In this context, it is imperative to have valid comparative frameworks for interpretation of lipid levels. The aim of this study is to present sex- and age-specific reference values on blood lipid levels in European children aged 2.0-10.9 years. METHODS: Fasting blood was obtained via either venipuncture or capillary sampling. In 13,579 European non-obese children (50.3% boys), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), TG and TC/HDL-C ratio levels were measured with a point-of-care analyser (Cholestech). Sex- and age-specific reference values were computed with the GAMLSS method with the statistical software R. RESULTS: Reference curves and 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile values are presented. HDL-C showed a positive trend with age, from 2 years onwards, but was relatively stable above the age of 7. For LDL-C and TC, linear but small age-related trends were seen. The TC/HDL-C values showed a gradual negative trend from the age of 2 up to 6 and were relatively stable afterwards. For TG, no age trend was found (P=0.285). Boys had higher mean HDL-C values than girls (1.414 vs 1.368 mmol l(-1)), and lower TC, LDL-C, TC/HDL-C and TG values (3.981 vs 4.087 mmol l(-1); 2.297 vs 2.435 mmol l(-1); 2.84 vs 3.01mmol l(-1);  and 0.509 vs 0.542 mmol l(-1), respectively). CONCLUSIONS: These new and recent references could serve as a European orientation of blood lipid values in children in the context of standard medical practice and for the purpose of public health screening.

24 Article Lim domain binding 2: a key driver of transendothelial migration of leukocytes and atherosclerosis. 2014

Shang, Ming-Mei / Talukdar, Husain A / Hofmann, Jennifer J / Niaudet, Colin / Asl, Hassan Foroughi / Jain, Rajeev K / Rossignoli, Aranzazu / Cedergren, Cecilia / Silveira, Angela / Gigante, Bruna / Leander, Karin / de Faire, Ulf / Hamsten, Anders / Ruusalepp, Arno / Melander, Olle / Ivert, Torbjörn / Michoel, Tom / Schadt, Eric E / Betsholtz, Christer / Skogsberg, Josefin / Björkegren, Johan L M. ·From the Division of Cardiovascular Genomics (M.M.S., H.A.T., H.F.A., A.R., C.C., J.S., J.L.M.B.), Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (M.M.S., H.A.T., J.J.H., C.N., H.F.A., A.R., C.C., C.B., J.S., J.L.M.B.), Computational Medicine Unit, Department of Medicine Solna, Center of Molecular Medicine (M.M.S.), and Department of Environmental Medicine (B.G., K.L., U.d.F.), Karolinska Institutet, Solna, Sweden · Clinical Gene Networks AB, Karolinska Science Park, Solna, Sweden (M.M.S., A.R., J.L.M.B.) · Division of Cardiovascular Genomics, Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia (R.K.J., A.R., J.L.M.B.) · Cardiovascular Genetics and Genomics, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden (A.S., A.H.) · Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia (A.R.) · Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Clinical Research Center, Skåne University Hospital, Malmö, Sweden (O.M.) · Department of Cardiothoracic Surgery and Anesthesiology and Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Sweden (T.I.) · School of Life Sciences-LifeNet, Freiburg Institute for Advanced Studies, University of Freiburg, Freiburg im Breisgau, Germany (T.M.) · The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, United Kingdom (T.M.) · and Institute for Genomics and Multi-Scale Biology, Mount Sinai School of Medicine, New York, NY (E.E.S., J.L.M.B.). ·Arterioscler Thromb Vasc Biol · Pubmed #24925974.

ABSTRACT: OBJECTIVE: Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis. APPROACH AND RESULTS: mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts. CONCLUSIONS: As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.

25 Article Discovery and refinement of loci associated with lipid levels. 2013

Willer, Cristen J / Schmidt, Ellen M / Sengupta, Sebanti / Peloso, Gina M / Gustafsson, Stefan / Kanoni, Stavroula / Ganna, Andrea / Chen, Jin / Buchkovich, Martin L / Mora, Samia / Beckmann, Jacques S / Bragg-Gresham, Jennifer L / Chang, Hsing-Yi / Demirkan, Ayşe / Den Hertog, Heleen M / Do, Ron / Donnelly, Louise A / Ehret, Georg B / Esko, Tõnu / Feitosa, Mary F / Ferreira, Teresa / Fischer, Krista / Fontanillas, Pierre / Fraser, Ross M / Freitag, Daniel F / Gurdasani, Deepti / Heikkilä, Kauko / Hyppönen, Elina / Isaacs, Aaron / Jackson, Anne U / Johansson, Åsa / Johnson, Toby / Kaakinen, Marika / Kettunen, Johannes / Kleber, Marcus E / Li, Xiaohui / Luan, Jian'an / Lyytikäinen, Leo-Pekka / Magnusson, Patrik K E / Mangino, Massimo / Mihailov, Evelin / Montasser, May E / Müller-Nurasyid, Martina / Nolte, Ilja M / O'Connell, Jeffrey R / Palmer, Cameron D / Perola, Markus / Petersen, Ann-Kristin / Sanna, Serena / Saxena, Richa / Service, Susan K / Shah, Sonia / Shungin, Dmitry / Sidore, Carlo / Song, Ci / Strawbridge, Rona J / Surakka, Ida / Tanaka, Toshiko / Teslovich, Tanya M / Thorleifsson, Gudmar / Van den Herik, Evita G / Voight, Benjamin F / Volcik, Kelly A / Waite, Lindsay L / Wong, Andrew / Wu, Ying / Zhang, Weihua / Absher, Devin / Asiki, Gershim / Barroso, Inês / Been, Latonya F / Bolton, Jennifer L / Bonnycastle, Lori L / Brambilla, Paolo / Burnett, Mary S / Cesana, Giancarlo / Dimitriou, Maria / Doney, Alex S F / Döring, Angela / Elliott, Paul / Epstein, Stephen E / Ingi Eyjolfsson, Gudmundur / Gigante, Bruna / Goodarzi, Mark O / Grallert, Harald / Gravito, Martha L / Groves, Christopher J / Hallmans, Göran / Hartikainen, Anna-Liisa / Hayward, Caroline / Hernandez, Dena / Hicks, Andrew A / Holm, Hilma / Hung, Yi-Jen / Illig, Thomas / Jones, Michelle R / Kaleebu, Pontiano / Kastelein, John J P / Khaw, Kay-Tee / Kim, Eric / Klopp, Norman / Komulainen, Pirjo / Kumari, Meena / Langenberg, Claudia / Lehtimäki, Terho / Lin, Shih-Yi / Lindström, Jaana / Loos, Ruth J F / Mach, François / McArdle, Wendy L / Meisinger, Christa / Mitchell, Braxton D / Müller, Gabrielle / Nagaraja, Ramaiah / Narisu, Narisu / Nieminen, Tuomo V M / Nsubuga, Rebecca N / Olafsson, Isleifur / Ong, Ken K / Palotie, Aarno / Papamarkou, Theodore / Pomilla, Cristina / Pouta, Anneli / Rader, Daniel J / Reilly, Muredach P / Ridker, Paul M / Rivadeneira, Fernando / Rudan, Igor / Ruokonen, Aimo / Samani, Nilesh / Scharnagl, Hubert / Seeley, Janet / Silander, Kaisa / Stančáková, Alena / Stirrups, Kathleen / Swift, Amy J / Tiret, Laurence / Uitterlinden, Andre G / van Pelt, L Joost / Vedantam, Sailaja / Wainwright, Nicholas / Wijmenga, Cisca / Wild, Sarah H / Willemsen, Gonneke / Wilsgaard, Tom / Wilson, James F / Young, Elizabeth H / Zhao, Jing Hua / Adair, Linda S / Arveiler, Dominique / Assimes, Themistocles L / Bandinelli, Stefania / Bennett, Franklyn / Bochud, Murielle / Boehm, Bernhard O / Boomsma, Dorret I / Borecki, Ingrid B / Bornstein, Stefan R / Bovet, Pascal / Burnier, Michel / Campbell, Harry / Chakravarti, Aravinda / Chambers, John C / Chen, Yii-Der Ida / Collins, Francis S / Cooper, Richard S / Danesh, John / Dedoussis, George / de Faire, Ulf / Feranil, Alan B / Ferrières, Jean / Ferrucci, Luigi / Freimer, Nelson B / Gieger, Christian / Groop, Leif C / Gudnason, Vilmundur / Gyllensten, Ulf / Hamsten, Anders / Harris, Tamara B / Hingorani, Aroon / Hirschhorn, Joel N / Hofman, Albert / Hovingh, G Kees / Hsiung, Chao Agnes / Humphries, Steve E / Hunt, Steven C / Hveem, Kristian / Iribarren, Carlos / Järvelin, Marjo-Riitta / Jula, Antti / Kähönen, Mika / Kaprio, Jaakko / Kesäniemi, Antero / Kivimaki, Mika / Kooner, Jaspal S / Koudstaal, Peter J / Krauss, Ronald M / Kuh, Diana / Kuusisto, Johanna / Kyvik, Kirsten O / Laakso, Markku / Lakka, Timo A / Lind, Lars / Lindgren, Cecilia M / Martin, Nicholas G / März, Winfried / McCarthy, Mark I / McKenzie, Colin A / Meneton, Pierre / Metspalu, Andres / Moilanen, Leena / Morris, Andrew D / Munroe, Patricia B / Njølstad, Inger / Pedersen, Nancy L / Power, Chris / Pramstaller, Peter P / Price, Jackie F / Psaty, Bruce M / Quertermous, Thomas / Rauramaa, Rainer / Saleheen, Danish / Salomaa, Veikko / Sanghera, Dharambir K / Saramies, Jouko / Schwarz, Peter E H / Sheu, Wayne H-H / Shuldiner, Alan R / Siegbahn, Agneta / Spector, Tim D / Stefansson, Kari / Strachan, David P / Tayo, Bamidele O / Tremoli, Elena / Tuomilehto, Jaakko / Uusitupa, Matti / van Duijn, Cornelia M / Vollenweider, Peter / Wallentin, Lars / Wareham, Nicholas J / Whitfield, John B / Wolffenbuttel, Bruce H R / Ordovas, Jose M / Boerwinkle, Eric / Palmer, Colin N A / Thorsteinsdottir, Unnur / Chasman, Daniel I / Rotter, Jerome I / Franks, Paul W / Ripatti, Samuli / Cupples, L Adrienne / Sandhu, Manjinder S / Rich, Stephen S / Boehnke, Michael / Deloukas, Panos / Kathiresan, Sekar / Mohlke, Karen L / Ingelsson, Erik / Abecasis, Gonçalo R / Anonymous3140771. ·Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Broad Institute, Program in Medical and Population Genetics, Cambridge, Massachusetts 02142, USA. · Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden. · Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1SA, Hinxton, United Kingdom. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Department of Genetics, University of North Carolina, Chapel Hill, NC 27599 USA. · Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave., Boston MA 02215, USA. · Harvard Medical School, Boston MA 02115, USA. · Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland. · Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. · Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School. Dundee, DD1 9SY, United Kingdom. · Cardiology, Department of Specialities of Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. · Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Estonian Genome Center of the University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. · Department of Genetics, Washington University School of Medicine, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom. · Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland, United Kingdom. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. · Hjelt Institute, Department of Public Health, University of Helsinki, Finland. · Centre For Paediatric Epidemiology and Biostatistics/MRC Centre of Epidemiology for Child Health, University College of London Institute of Child Health, London, United Kingdom. · Centre for Medical Systems Biology, Leiden, the Netherlands. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. · Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London, London, UK. · Biocenter Oulu, University of Oulu, Oulu, Finland. · Institute of Health Sciences, University of Oulu, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland. · Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. · Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany. · Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 7-11, 68167 Mannheim, Germany. · Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · MRC Epidemiology Unit, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland. · Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. · Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands. · Division of Endocrinology, Children's Hospital Boston, Massachusetts 02115, USA. · Division of Genetics, Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA. · Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, 09042, Italy. · Massachusetts General Hospital/Broad Institute, Harvard University, Cambridge, MA, USA. · Center for Neurobehavioral Genetics, The Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA. · Genetic Epidemiology Group, Deparment of Epidemiology and Public Health, UCL, London WC1E 6BT, United Kingdom. · Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Scania University Hosptial, Malmö, Sweden. · Department of Odontology, Umeå University, Umeå, Sweden. · Department of Public Health and Primary Care, Unit of Medicine, Umeå University, Umeå, Sweden. · Dipartimento di Scienze Biomediche, Universita di Sassari, 07100 SS, Italy. · Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. · Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. · Clinical Research Branch, National Institute Health, Baltimore, MD, USA. · deCODE Genetics/Amgen, 101 Reykjavik, Iceland. · Department of Genetics, University of Pennsylvania - School of Medicine, Philadelphia PA, 19104, USA. · Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania - School of Medicine, Philadelphia PA, 19104, USA. · Human Genetics Center, University of Texas Health Science Center - School of Public Health, Houston, TX 77030, USA. · HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA. · MRC Unit for Lifelong Health and Ageing, 33 Bedford Place, London, WC1B 5JU, United Kingdom. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Ealing Hospital, Southall, Middlesex UB1 3HW, United Kingdom. · MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda. · University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Level 4, Institute of Metabolic Science Box 289 Addenbrooke's Hospital Cambridge CB2 OQQ, UK. · Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. · Department of Experimental Medicine, University of Milano Bicocca, Italy. · MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD 20782, USA. · Research Centre on Public Health, University of Milano Bicocca, Italy. · Department of Dietetics-Nutrition, Harokopio University, 70 El. Venizelou Str, Athens, Greece. · Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK. · The Laboratory in Mjodd, 108 Reykjavik, Iceland. · Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. · Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LJ, United Kingdom. · Department of Public Health and Clinical Medicine, Nutritional research, Umeå University, Umeå, Sweden. · Department of Clinical Sciences/Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. · Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany. · Division of Endocrinology & Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. · Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan. · Diabetes Prevention Unit, National Institute for Health and Welfare, 00271 Helsinki, Finland. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, USA. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at ount Sinai, New York, USA. · The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York. · School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. · Institute for Medical Informatics and Biometrics, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany. · Laboratory of Genetics, National Institute on Aging, Baltimore, MD21224, USA. · Department of Clinical Pharmacology, University of Tampere School of Medicine, Tamperew 33014, Finland. · Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland. · Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. · Department of Clinical Biochemistry, Landspitali University Hospital, 101 Reykjavik, Iceland. · Department of Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United ingdom. · Department of Statistical Sciences, University College of London, London, United Kingdom. · National Institute for Health and Welfare, Oulu, Finland. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Building 421, Translational Research Center, Philadelphia, PA 19104-5158, USA. · Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Building 421, Translational Research Center, Philadelphia, PA 19104-5158, USA. · Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. · Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging NCHA), Leiden, The Netherlands. · Department of Clinical Sciences/Clinical Chemistry, University of Oulu, Oulu, Finland. · National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, UK. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria. · School of International Development, University of East Anglia, Norwich NR4 7TJ, United Kingdom. · University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland. · INSERM UMRS 937, Pierre and Marie Curie University, Paris, France. · Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, The Netherlands. · LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Biological Psychology, VU Univ, Amsterdam, The Netherlands. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. · Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Faculty of Medicine, Strasbourg, France. · Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. · Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy. · Chemical Pathology, Department of Pathology, University of the West Indies, Mona, Kingston 7, Jamaica. · Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 10, 1010 Lausanne, Switzerland. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University Medical Centre, Ulm, Germany. · Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. · Department of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany. · Ministry of Health, Victoria, Republic of Seychelles. · Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland. · Imperial College Healthcare NHS Trust, London, United Kingdom. · Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Medicine, University of California Los Angeles, Los Angeles, California, USA. · Department of Preventive Medicine and Epidemiology, Loyola University Medical School, Maywood, Illinois 60153, USA. · Office of Population Studies Foundation, University of San Carlos, Talamban, Cebu City, Philippines. · Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France. · Department of Psychiatry, University of California, Los Angeles, USA. · Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden. · Department of Medicine, Helsinki University Hospital, FI-00029 Helsinki, Finland. · Icelandic Heart Association, Kopavogur, Iceland. · Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Ageing, Bethesda, MD, USA. · Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. · Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Science, University College London, London, United Kingdom. · Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. · Kaiser Permanente, Division of Research, Oakland, CA, USA. · Unit of Primary Care, Oulu University Hospital, Oulu, Finland. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland. · Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33014, Finland. · Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. · Institute of Clinical Medicine, Department of Medicine, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland. · National Heart & Lung Institute, Imperial College London, Hammersmith Hospital, London, United Kingdom. · Children's Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609, USA. · Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland. · Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark. · Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark. · Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Finland. · Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Queensland Institute of Medical Research, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia. · Synlab Academy, Synlab Services GmbH,Gottlieb-Daimler-Straße 25, 68165 Mannheim, Germany. · Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Kingston 7, Jamaica. · U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, 75006 Paris, France. · Department of Medicine, Kuopio University Hospital, Kuopio, Finland. · Department of Neurology, General Central Hospital, Bolzano, Italy. · Department of Neurology, University of Lübeck, Lübeck, Germany. · Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA. · Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Department of Medicine, University of Pennsylvania, USA. · Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland. · South Karelia Central Hospital, Lappeenranta, Finland. · Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland. · Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland. · Division of Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. · Department of Pharmacological Sciences, University of Milan, Monzino Cardiology Center, IRCCS, Milan, Italy. · Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. · King Abdulaziz University, Faculty of Medicine, Jeddah 21589, Saudi Arabia. · Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, 28046. · Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland. · Research Unit, Kuopio University Hospital, Kuopio, Finland. · Department of Medicine, Lausanne University Hospital, Switzerland. · Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for rdiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Department of Nutrition, Harvard School of Public Health, Boston, MA, USA. · Framingham Heart Study, Framingham, MA, USA. · Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ·Nat Genet · Pubmed #24097068.

ABSTRACT: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

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