Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Coronary Artery Disease: HELP
Articles by Unnur Thorsteinsdottir
Based on 19 articles published since 2009
(Why 19 articles?)
||||

Between 2009 and 2019, Unnur Thorsteinsdottir wrote the following 19 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
1 Review Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. 2014

Dichgans, Martin / Malik, Rainer / König, Inke R / Rosand, Jonathan / Clarke, Robert / Gretarsdottir, Solveig / Thorleifsson, Gudmar / Mitchell, Braxton D / Assimes, Themistocles L / Levi, Christopher / O'Donnell, Christopher J / Fornage, Myriam / Thorsteinsdottir, Unnur / Psaty, Bruce M / Hengstenberg, Christian / Seshadri, Sudha / Erdmann, Jeanette / Bis, Joshua C / Peters, Annette / Boncoraglio, Giorgio B / März, Winfried / Meschia, James F / Kathiresan, Sekar / Ikram, M Arfan / McPherson, Ruth / Stefansson, Kari / Sudlow, Cathie / Reilly, Muredach P / Thompson, John R / Sharma, Pankaj / Hopewell, Jemma C / Chambers, John C / Watkins, Hugh / Rothwell, Peter M / Roberts, Robert / Markus, Hugh S / Samani, Nilesh J / Farrall, Martin / Schunkert, Heribert / Anonymous2810776 / Anonymous2820776 / Anonymous2830776 / Anonymous2840776. ·From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (M.D., R. Malik) · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.) · Institut für Medizinische Biometrie und Statistik (I.R.K.), and Institut für integrative und experimentelle Genomik (J.E.), Universität zu Lübeck, Lübeck, Germany · Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Germany (I.R.K.) · Department of Neurology and Center for Human Genetic Research (J.R.), and Cardiology Division (C.J.O.D.), Massachusetts General Hospital, Boston · Harvard Medical School, Boston, MA (J.R.) · Program in Medical and Population Genetics (J.R.), and Program in Medical and Population Genetics (S.K.), Broad Institute of Harvard and MIT, Cambridge, MA · Clinical Trial Service Unit and Epidemiological Studies Unit (R.C., J.C.H.), Wellcome Trust Centre for Human Genetics (H.W., M. Farrall), Department of Cardiovascular Medicine (M. Farrall), and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience (P.M.R.), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom · deCODE Genetics, Reykjavik, Iceland (S.G., G.T., U.T., K.S.) · Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M.) · Department of Medicine, Stanford University School of Medicine, Stanford, CA (T.L.A.) · Center for Translational Neuroscience and Mental Health Research, University of Newcastle, New South Wales, Australia (C.L.) · Hunter Medical Research Institute, New South Wales, Australia (C.L.) · National Heart, Lung and Blood Institute and NHLBI's Framingham Heart Study, MA (C.J.O.D., S.S.) · University of Texas Health Science Center at Houston (M. Fornage) · Cardiovascular Health Research Unit, Department of Epidemiology (B.M.P.), Department of Medicine (B.M.P.), Department of Health Services (B.M.P.), and Cardiovascular Health Research Unit, Department of Medicine (J.C.B.), University ·Stroke · Pubmed #24262325.

ABSTRACT: BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

2 Article Genome-wide analysis yields new loci associating with aortic valve stenosis. 2018

Helgadottir, Anna / Thorleifsson, Gudmar / Gretarsdottir, Solveig / Stefansson, Olafur A / Tragante, Vinicius / Thorolfsdottir, Rosa B / Jonsdottir, Ingileif / Bjornsson, Thorsteinn / Steinthorsdottir, Valgerdur / Verweij, Niek / Nielsen, Jonas B / Zhou, Wei / Folkersen, Lasse / Martinsson, Andreas / Heydarpour, Mahyar / Prakash, Siddharth / Oskarsson, Gylfi / Gudbjartsson, Tomas / Geirsson, Arnar / Olafsson, Isleifur / Sigurdsson, Emil L / Almgren, Peter / Melander, Olle / Franco-Cereceda, Anders / Hamsten, Anders / Fritsche, Lars / Lin, Maoxuan / Yang, Bo / Hornsby, Whitney / Guo, Dongchuan / Brummett, Chad M / Abecasis, Gonçalo / Mathis, Michael / Milewicz, Dianna / Body, Simon C / Eriksson, Per / Willer, Cristen J / Hveem, Kristian / Newton-Cheh, Christopher / Smith, J Gustav / Danielsen, Ragnar / Thorgeirsson, Gudmundur / Thorsteinsdottir, Unnur / Gudbjartsson, Daniel F / Holm, Hilma / Stefansson, Kari. ·deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. anna.helgadottir@decode.is. · deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. · Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands. · Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, 48109, MI, USA. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA. · Cardiovascular Medicine Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden. · Department of Bioinformatics, Technical University of Denmark, Copenhagen, 2800, Denmark. · Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, 22185, Sweden. · Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. · Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA. · Childrens Hospital, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland. · Department of Surgery and Cardiothoracic Surgery, Landspitali National University Hospital, Reykjavik, 101, Iceland. · Section of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, 06510, CT, USA. · Department of Clinical Biochemistry, Landspitali National University Hospital, Reykjavik, 101, Iceland. · Heilsugaeslan Solvangi, Hafnarfjördur, 220, Iceland. · Department of Family Medicine, University of Iceland, Reykjavik, 101, Iceland. · Department of Clinical Sciences, Lund University, Malmö, 22185, Sweden. · Department of Internal Medicine, Skåne University Hospital, Malmö, 22185, Sweden. · Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, 17176, Sweden. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7491, Norway. · K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, 7491, Norway. · Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, 48105, USA. · Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA. · Department of Anesthesiology, University of Michigan, Ann Arbor, MI, 48105, USA. · Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA. · Medicine Services, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, TX, 77030, USA. · Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. · Massachusetts General Hospital, Harvard Medical School, Broad Institute of Harvard and MIT, Boston, MA, 02114, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA. · Department of Internal Medicine, Division of Cardiology, Landspitali National University Hospital of Iceland, Reykjavik, 101, Iceland. · School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland. · deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. kstefans@decode.is. · Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is. ·Nat Commun · Pubmed #29511194.

ABSTRACT: Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10

3 Article A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease. 2017

Bjornsson, Eythor / Helgason, Hannes / Halldorsson, Gisli / Helgadottir, Anna / Gylfason, Arnaldur / Kehr, Birte / Jonasdottir, Adalbjorg / Jonasdottir, Aslaug / Sigurdsson, Asgeir / Oddsson, Asmundur / Thorleifsson, Gudmar / Magnusson, Olafur Th / Gretarsdottir, Solveig / Zink, Florian / Kristjansson, Ragnar P / Asgeirsdottir, Margret / Swinkels, Dorine W / Kiemeney, Lambertus A / Eyjolfsson, Gudmundur I / Sigurdardottir, Olof / Masson, Gisli / Olafsson, Isleifur / Thorgeirsson, Gudmundur / Holm, Hilma / Thorsteinsdottir, Unnur / Gudbjartsson, Daniel F / Sulem, Patrick / Stefansson, Kari. ·deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. · Faculty of Medicine. · School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. · Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine, Nijmegen, The Netherlands. · Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. · The Laboratory in Mjodd, Reykjavik, Iceland. · Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland. · Department of Clinical Biochemistry. · Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. ·Hum Mol Genet · Pubmed #28398513.

ABSTRACT: Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.

4 Article Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. 2016

Nioi, Paul / Sigurdsson, Asgeir / Thorleifsson, Gudmar / Helgason, Hannes / Agustsdottir, Arna B / Norddahl, Gudmundur L / Helgadottir, Anna / Magnusdottir, Audur / Jonasdottir, Aslaug / Gretarsdottir, Solveig / Jonsdottir, Ingileif / Steinthorsdottir, Valgerdur / Rafnar, Thorunn / Swinkels, Dorine W / Galesloot, Tessel E / Grarup, Niels / Jørgensen, Torben / Vestergaard, Henrik / Hansen, Torben / Lauritzen, Torsten / Linneberg, Allan / Friedrich, Nele / Krarup, Nikolaj T / Fenger, Mogens / Abildgaard, Ulrik / Hansen, Peter R / Galløe, Anders M / Braund, Peter S / Nelson, Christopher P / Hall, Alistair S / Williams, Michael J A / van Rij, Andre M / Jones, Gregory T / Patel, Riyaz S / Levey, Allan I / Hayek, Salim / Shah, Svati H / Reilly, Muredach / Eyjolfsson, Gudmundur I / Sigurdardottir, Olof / Olafsson, Isleifur / Kiemeney, Lambertus A / Quyyumi, Arshed A / Rader, Daniel J / Kraus, William E / Samani, Nilesh J / Pedersen, Oluf / Thorgeirsson, Gudmundur / Masson, Gisli / Holm, Hilma / Gudbjartsson, Daniel / Sulem, Patrick / Thorsteinsdottir, Unnur / Stefansson, Kari. ·From deCODE Genetics-Amgen (P.N., A.S., G. Thorleifsson, H. Helgason, A.B.A., G.L.N., A.H., A.M., A.J., S.G., I.J., V.S., T.R., G.M., H. Holm, D.G., P.S., U.T., K.S.), Faculty of Medicine (A.H., I.J., G. Thorgeirsson, U.T., K.S.) and School of Engineering and Natural Sciences (H. Helgason, D.G.), University of Iceland, the Laboratory in Mjodd (G.I.E.), and the Department of Clinical Biochemistry (I.O.) and Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, H. Holm), Landspitali, National University Hospital of Iceland, Reykjavik, and the Department of Clinical Biochemistry, Akureyri Hospital, Akureyri (O.S.) - all in Iceland · Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine (D.W.S.), Radboud Institute for Health Sciences (T.E.G., L.A.K.), and the Department of Health Evidence (L.A.K.), Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands · Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics (N.G., H.V., T.H., N.T.K., O.P.), and Institute of Public Health, Faculty of Health and Medical Science (T.J., A.L.), University of Copenhagen, and Research Center for Prevention and Health, Capital Region of Denmark (T.J., A.L.), Copenhagen, Faculty of Medicine, University of Aalborg, Aalborg (T.J.), Faculty of Health Sciences, University of Southern Denmark, Odense (T.H.), Department of Public Health, Section of General Practice, University of Aarhus, Aarhus (T.L.), Department of Clinical Experimental Research, Rigshospitalet, Glostrup (A.L.), Department of Clinical Biochemistry, University Hospital of Copenhagen at Hvidovre, Hvidovre (M.F.), Department of Cardiology, Gentofte University Hospital, Hellerup (U.A., P.R.H., A.M.G.), and Department of Cardiology, Roskilde Hospital, Roskilde (A.M.G.) - all in Denmark · Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany (N.F.) · Department of Cardiovascular Sciences, Uni ·N Engl J Med · Pubmed #27192541.

ABSTRACT: BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).

5 Article Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. 2016

Helgadottir, Anna / Gretarsdottir, Solveig / Thorleifsson, Gudmar / Hjartarson, Eirikur / Sigurdsson, Asgeir / Magnusdottir, Audur / Jonasdottir, Aslaug / Kristjansson, Helgi / Sulem, Patrick / Oddsson, Asmundur / Sveinbjornsson, Gardar / Steinthorsdottir, Valgerdur / Rafnar, Thorunn / Masson, Gisli / Jonsdottir, Ingileif / Olafsson, Isleifur / Eyjolfsson, Gudmundur I / Sigurdardottir, Olof / Daneshpour, Maryam S / Khalili, Davood / Azizi, Fereidoun / Swinkels, Dorine W / Kiemeney, Lambertus / Quyyumi, Arshed A / Levey, Allan I / Patel, Riyaz S / Hayek, Salim S / Gudmundsdottir, Ingibjorg J / Thorgeirsson, Gudmundur / Thorsteinsdottir, Unnur / Gudbjartsson, Daniel F / Holm, Hilma / Stefansson, Kari. ·deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Department of Immunology, Landspítali-National University Hospital, Reykjavik, Iceland. · Department of Clinical Biochemistry, Landspítali-National University Hospital, Reykjavik, Iceland. · Laboratory in Mjódd (RAM), Reykjavik, Iceland. · Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland. · Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. · Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. · Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. · Department for Laboratory Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. · Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands. · Emory University School of Medicine, Atlanta, Georgia, USA. · Division of Cardiology, Department of Internal Medicine, Landspítali-National University Hospital, Reykjavik, Iceland. · School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. ·Nat Genet · Pubmed #27135400.

ABSTRACT: Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.

6 Article A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease. 2015

Gretarsdottir, Solveig / Helgason, Hannes / Helgadottir, Anna / Sigurdsson, Asgeir / Thorleifsson, Gudmar / Magnusdottir, Audur / Oddsson, Asmundur / Steinthorsdottir, Valgerdur / Rafnar, Thorunn / de Graaf, Jacqueline / Daneshpour, Maryam S / Hedayati, Mehdi / Azizi, Fereidoun / Grarup, Niels / Jørgensen, Torben / Vestergaard, Henrik / Hansen, Torben / Eyjolfsson, Gudmundur / Sigurdardottir, Olof / Olafsson, Isleifur / Kiemeney, Lambertus A / Pedersen, Oluf / Sulem, Patrick / Thorgeirsson, Gudmundur / Gudbjartsson, Daniel F / Holm, Hilma / Thorsteinsdottir, Unnur / Stefansson, Kari. ·deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. · deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. · deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. · Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran. · Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark; Institute of Public Health and Medical Science, University of Copenhagen, Copenhagen, Denmark. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. · The Laboratory in Mjodd, RAM, Reykjavik, Iceland. · Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland. · Department of Clinical Biochemistry, Landspitali, National University Hospital, Reykjavik, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. · deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. ·PLoS Genet · Pubmed #26327206.

ABSTRACT: Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.

7 Article Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk. 2015

Jansen, Henning / Loley, Christina / Lieb, Wolfgang / Pencina, Michael J / Nelson, Christopher P / Kathiresan, Sekar / Peloso, Gina M / Voight, Benjamin F / Reilly, Muredach P / Assimes, Themistocles L / Boerwinkle, Eric / Hengstenberg, Christian / Laaksonen, Reijo / McPherson, Ruth / Roberts, Robert / Thorsteinsdottir, Unnur / Peters, Annette / Gieger, Christian / Rawal, Rajesh / Thompson, John R / König, Inke R / Anonymous2050833 / Vasan, Ramachandran S / Erdmann, Jeanette / Samani, Nilesh J / Schunkert, Heribert. ·Deutsches Herzzentrum and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Technische Universität München, Munich, Germany. · Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Institut für Epidemiologie, Universität zu Kiel, Kiel, Germany. · Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Durham, NC, USA. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, UK; Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, LE3 9QP, UK. · Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, MA, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA. · The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. · University of Texas Health Science Center, Human Genetics Center and Institute of Molecular Medicine, Houston, TX, USA. · Science Center, Tampere University Hospital, Tampere, Finland. · The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada. · deCODE Genetics and University of Iceland, Faculty of Medicine, 101, Reykjavik, Iceland. · Institut für Epidemiologie II, Helmholtz Zentrum München, Neuherberg, Germany; Munich Heart Alliance, Munich, Germany. · Department of Health Sciences, University of Leicester, Leicester, UK. · School of Medicine, Section of Preventive Medicine and Epidemiology, Boston University, Boston, MA, USA. · Institut für Integrative und Experimentelle Genomik Universität zu Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany. ·Atherosclerosis · Pubmed #26074316.

ABSTRACT: BACKGROUND: The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. METHODS AND RESULTS: We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. CONCLUSIONS: Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.

8 Article Common sequence variants associated with coronary artery disease correlate with the extent of coronary atherosclerosis. 2015

Bjornsson, Eythor / Gudbjartsson, Daniel F / Helgadottir, Anna / Gudnason, Thorarinn / Gudbjartsson, Tomas / Eyjolfsson, Kristjan / Patel, Riyaz S / Ghasemzadeh, Nima / Thorleifsson, Gudmar / Quyyumi, Arshed A / Thorsteinsdottir, Unnur / Thorgeirsson, Gudmundur / Stefansson, Kari. ·From the Faculty of Medicine (E.B., A.H., T.G., U.T., G.T., K.S.) and Department of Engineering and Natural Sciences (D.F.G.), University of Iceland, Reykjavik, Iceland · deCODE Genetics, Reykjavik, Iceland (E.B., D.F.G., A.H., G.T., U.T., K.S.) · Department of Medicine (T.G., K.E., G.T.), and Department of Surgery (T.G.), Landspitali University Hospital, Reykjavik, Iceland · Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.P., N.G., A.A.Q.) · and Institute of Cardiovascular Sciences, University College London, London, United Kingdom (R.S.P.). ·Arterioscler Thromb Vasc Biol · Pubmed #25882067.

ABSTRACT: OBJECTIVE: Single-nucleotide polymorphisms predisposing to coronary artery disease (CAD) have been shown to predict cardiovascular risk in healthy individuals when combined into a genetic risk score (GRS). We examined whether the cumulative burden of known genetic risk variants associated with risk of CAD influences the development and progression of coronary atherosclerosis. APPROACH AND RESULTS: We investigated the combined effects of all known CAD variants in a cross-sectional study of 8622 Icelandic patients with angiographically significant CAD (≥ 50% diameter stenosis). We constructed a GRS based on 50 CAD variants and tested for association with the number of diseased coronary arteries on angiography. In models adjusted for traditional cardiovascular risk factors, the GRS associated significantly with CAD extent (difference per SD increase in GRS, 0.076; P=7.3 × 10(-17)). When compared with the bottom GRS quintile, patients in the top GRS quintile were roughly 1.67× more likely to have multivessel disease (odds ratio, 1.67; 95% confidence interval, 1.45-1.94). The GRS significantly improved prediction of multivessel disease over traditional cardiovascular risk factors (χ(2) likelihood ratio 48.1; P<0.0001) and modestly improved discrimination, as estimated by the C-statistic (without GRS versus with GRS, 64.0% versus 64.8%) and the integrated discrimination improvement (0.52%). Furthermore, the GRS associated with an earlier age at diagnosis of angiographic CAD. These findings were replicated in an independent sample from the Emory Biobank study (n=1853). CONCLUSIONS: When combined into a single GRS, known genetic risk variants for CAD contribute significantly to the extent of coronary atherosclerosis in patients with significant angiographic disease.

9 Article Genetically determined height and coronary artery disease. 2015

Nelson, Christopher P / Hamby, Stephen E / Saleheen, Danish / Hopewell, Jenna C / Zeng, Lingyao / Assimes, Themistocles L / Kanoni, Stavroula / Willenborg, Christina / Burgess, Stephen / Amouyel, Phillipe / Anand, Sonia / Blankenberg, Stefan / Boehm, Bernhard O / Clarke, Robert J / Collins, Rory / Dedoussis, George / Farrall, Martin / Franks, Paul W / Groop, Leif / Hall, Alistair S / Hamsten, Anders / Hengstenberg, Christian / Hovingh, G Kees / Ingelsson, Erik / Kathiresan, Sekar / Kee, Frank / König, Inke R / Kooner, Jaspal / Lehtimäki, Terho / März, Winifred / McPherson, Ruth / Metspalu, Andres / Nieminen, Markku S / O'Donnell, Christopher J / Palmer, Colin N A / Peters, Annette / Perola, Markus / Reilly, Muredach P / Ripatti, Samuli / Roberts, Robert / Salomaa, Veikko / Shah, Svati H / Schreiber, Stefan / Siegbahn, Agneta / Thorsteinsdottir, Unnur / Veronesi, Giovani / Wareham, Nicholas / Willer, Cristen J / Zalloua, Pierre A / Erdmann, Jeanette / Deloukas, Panos / Watkins, Hugh / Schunkert, Heribert / Danesh, John / Thompson, John R / Samani, Nilesh J / Anonymous2660826. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25853659.

ABSTRACT: BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

10 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.

11 Article Common variants associated with plasma triglycerides and risk for coronary artery disease. 2013

Do, Ron / Willer, Cristen J / Schmidt, Ellen M / Sengupta, Sebanti / Gao, Chi / 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 / 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, Asa / 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 / Eyjolfsson, Gudmundur Ingi / 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 / Altshuler, David / 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 / Mohlke, Karen L / Ingelsson, Erik / Abecasis, Goncalo R / Daly, Mark J / Neale, Benjamin M / Kathiresan, Sekar. ·1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. ·Nat Genet · Pubmed #24097064.

ABSTRACT: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

12 Article Genetic predisposition to higher blood pressure increases coronary artery disease risk. 2013

Lieb, Wolfgang / Jansen, Henning / Loley, Christina / Pencina, Michael J / Nelson, Christopher P / Newton-Cheh, Christopher / Kathiresan, Sekar / Reilly, Muredach P / Assimes, Themistocles L / Boerwinkle, Eric / Hall, Alistair S / Hengstenberg, Christian / Laaksonen, Reijo / McPherson, Ruth / Thorsteinsdottir, Unnur / Ziegler, Andreas / Peters, Annette / Thompson, John R / König, Inke R / Erdmann, Jeanette / Samani, Nilesh J / Vasan, Ramachandran S / Schunkert, Heribert / Anonymous4971162. ·University Clinic Schleswig Holstein, Institute of Epidemiology, Campus Kiel, Germany. ·Hypertension · Pubmed #23478099.

ABSTRACT: Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

13 Article Large-scale association analysis identifies new risk loci for coronary artery disease. 2013

Anonymous5600743 / Deloukas, Panos / Kanoni, Stavroula / Willenborg, Christina / Farrall, Martin / Assimes, Themistocles L / Thompson, John R / Ingelsson, Erik / Saleheen, Danish / Erdmann, Jeanette / Goldstein, Benjamin A / Stirrups, Kathleen / König, Inke R / Cazier, Jean-Baptiste / Johansson, Asa / Hall, Alistair S / Lee, Jong-Young / Willer, Cristen J / Chambers, John C / Esko, Tõnu / Folkersen, Lasse / Goel, Anuj / Grundberg, Elin / Havulinna, Aki S / Ho, Weang K / Hopewell, Jemma C / Eriksson, Niclas / Kleber, Marcus E / Kristiansson, Kati / Lundmark, Per / Lyytikäinen, Leo-Pekka / Rafelt, Suzanne / Shungin, Dmitry / Strawbridge, Rona J / Thorleifsson, Gudmar / Tikkanen, Emmi / Van Zuydam, Natalie / Voight, Benjamin F / Waite, Lindsay L / Zhang, Weihua / Ziegler, Andreas / Absher, Devin / Altshuler, David / Balmforth, Anthony J / Barroso, Inês / Braund, Peter S / Burgdorf, Christof / Claudi-Boehm, Simone / Cox, David / Dimitriou, Maria / Do, Ron / Anonymous5610743 / Anonymous5620743 / Doney, Alex S F / El Mokhtari, NourEddine / Eriksson, Per / Fischer, Krista / Fontanillas, Pierre / Franco-Cereceda, Anders / Gigante, Bruna / Groop, Leif / Gustafsson, Stefan / Hager, Jörg / Hallmans, Göran / Han, Bok-Ghee / Hunt, Sarah E / Kang, Hyun M / Illig, Thomas / Kessler, Thorsten / Knowles, Joshua W / Kolovou, Genovefa / Kuusisto, Johanna / Langenberg, Claudia / Langford, Cordelia / Leander, Karin / Lokki, Marja-Liisa / Lundmark, Anders / McCarthy, Mark I / Meisinger, Christa / Melander, Olle / Mihailov, Evelin / Maouche, Seraya / Morris, Andrew D / Müller-Nurasyid, Martina / Anonymous5630743 / Nikus, Kjell / Peden, John F / Rayner, N William / Rasheed, Asif / Rosinger, Silke / Rubin, Diana / Rumpf, Moritz P / Schäfer, Arne / Sivananthan, Mohan / Song, Ci / Stewart, Alexandre F R / Tan, Sian-Tsung / Thorgeirsson, Gudmundur / van der Schoot, C Ellen / Wagner, Peter J / Anonymous5640743 / Wells, George A / Wild, Philipp S / Yang, Tsun-Po / Amouyel, Philippe / Arveiler, Dominique / Basart, Hanneke / Boehnke, Michael / Boerwinkle, Eric / Brambilla, Paolo / Cambien, Francois / Cupples, Adrienne L / de Faire, Ulf / Dehghan, Abbas / Diemert, Patrick / Epstein, Stephen E / Evans, Alun / Ferrario, Marco M / Ferrières, Jean / Gauguier, Dominique / Go, Alan S / Goodall, Alison H / Gudnason, Villi / Hazen, Stanley L / Holm, Hilma / Iribarren, Carlos / Jang, Yangsoo / Kähönen, Mika / Kee, Frank / Kim, Hyo-Soo / Klopp, Norman / Koenig, Wolfgang / Kratzer, Wolfgang / Kuulasmaa, Kari / Laakso, Markku / Laaksonen, Reijo / Lee, Ji-Young / Lind, Lars / Ouwehand, Willem H / Parish, Sarah / Park, Jeong E / Pedersen, Nancy L / Peters, Annette / Quertermous, Thomas / Rader, Daniel J / Salomaa, Veikko / Schadt, Eric / Shah, Svati H / Sinisalo, Juha / Stark, Klaus / Stefansson, Kari / Trégouët, David-Alexandre / Virtamo, Jarmo / Wallentin, Lars / Wareham, Nicholas / Zimmermann, Martina E / Nieminen, Markku S / Hengstenberg, Christian / Sandhu, Manjinder S / Pastinen, Tomi / Syvänen, Ann-Christine / Hovingh, G Kees / Dedoussis, George / Franks, Paul W / Lehtimäki, Terho / Metspalu, Andres / Zalloua, Pierre A / Siegbahn, Agneta / Schreiber, Stefan / Ripatti, Samuli / Blankenberg, Stefan S / Perola, Markus / Clarke, Robert / Boehm, Bernhard O / O'Donnell, Christopher / Reilly, Muredach P / März, Winfried / Collins, Rory / Kathiresan, Sekar / Hamsten, Anders / Kooner, Jaspal S / Thorsteinsdottir, Unnur / Danesh, John / Palmer, Colin N A / Roberts, Robert / Watkins, Hugh / Schunkert, Heribert / Samani, Nilesh J. · ·Nat Genet · Pubmed #23202125.

ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

14 Article Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. 2012

Helgadottir, Anna / Gretarsdottir, Solveig / Thorleifsson, Gudmar / Holm, Hilma / Patel, Riyaz S / Gudnason, Thorarinn / Jones, Gregory T / van Rij, Andre M / Eapen, Danny J / Baas, Annette F / Tregouet, David-Alexandre / Morange, Pierre-Emmanuel / Emmerich, Joseph / Lindblad, Bengt / Gottsäter, Anders / Kiemeny, Lambertus A / Lindholt, Jes S / Sakalihasan, Natzi / Ferrell, Robert E / Carey, David J / Elmore, James R / Tsao, Philip S / Grarup, Niels / Jørgensen, Torben / Witte, Daniel R / Hansen, Torben / Pedersen, Oluf / Pola, Roberto / Gaetani, Eleonora / Magnadottir, Hulda B / Wijmenga, Cisca / Tromp, Gerard / Ronkainen, Antti / Ruigrok, Ynte M / Blankensteijn, Jan D / Mueller, Thomas / Wells, Philip S / Corral, Javier / Soria, Jose Manuel / Souto, Juan Carlos / Peden, John F / Jalilzadeh, Shapour / Mayosi, Bongani M / Keavney, Bernard / Strawbridge, Rona J / Sabater-Lleal, Maria / Gertow, Karl / Baldassarre, Damiano / Nyyssönen, Kristiina / Rauramaa, Rainer / Smit, Andries J / Mannarino, Elmo / Giral, Philippe / Tremoli, Elena / de Faire, Ulf / Humphries, Steve E / Hamsten, Anders / Haraldsdottir, Vilhelmina / Olafsson, Isleifur / Magnusson, Magnus K / Samani, Nilesh J / Levey, Allan I / Markus, Hugh S / Kostulas, Konstantinos / Dichgans, Martin / Berger, Klaus / Kuhlenbäumer, Gregor / Ringelstein, E Bernd / Stoll, Monika / Seedorf, Udo / Rothwell, Peter M / Powell, Janet T / Kuivaniemi, Helena / Onundarson, Pall T / Valdimarsson, Einar / Matthiasson, Stefan E / Gudbjartsson, Daniel F / Thorgeirsson, Guðmundur / Quyyumi, Arshed A / Watkins, Hugh / Farrall, Martin / Thorsteinsdottir, Unnur / Stefansson, Kari. ·Population Genomics, deCODE Genetics, Reykjavik, Iceland. annah@decode.is ·J Am Coll Cardiol · Pubmed #22898070.

ABSTRACT: OBJECTIVES: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND: It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. METHODS: The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). RESULTS: LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). CONCLUSIONS: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

15 Article Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression. 2011

Faraday, Nauder / Yanek, Lisa R / Yang, Xiao Ping / Mathias, Rasika / Herrera-Galeano, J Enrique / Suktitipat, Bhoom / Qayyum, Rehan / Johnson, Andrew D / Chen, Ming-Huei / Tofler, Geoffrey H / Ruczinski, Ingo / Friedman, Alan D / Gylfason, Arnaldur / Thorsteinsdottir, Unnur / Bray, Paul F / O'Donnell, Christopher J / Becker, Diane M / Becker, Lewis C. ·Department of Anesthesiology and Critical Care Medicine,J ohns Hopkins University School of Medicine, Baltimore, MD, USA. nfaraday@jhmi.edu ·Blood · Pubmed #21791418.

ABSTRACT: Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for ≤ 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 × 10⁻⁸) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 × 10⁻²⁷) and in an independent sample of 2755 persons of European descent (P = 1.64 × 10⁻⁵). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 × 10⁻⁶) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype.

16 Article Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. 2011

Schunkert, Heribert / König, Inke R / Kathiresan, Sekar / Reilly, Muredach P / Assimes, Themistocles L / Holm, Hilma / Preuss, Michael / Stewart, Alexandre F R / Barbalic, Maja / Gieger, Christian / Absher, Devin / Aherrahrou, Zouhair / Allayee, Hooman / Altshuler, David / Anand, Sonia S / Andersen, Karl / Anderson, Jeffrey L / Ardissino, Diego / Ball, Stephen G / Balmforth, Anthony J / Barnes, Timothy A / Becker, Diane M / Becker, Lewis C / Berger, Klaus / Bis, Joshua C / Boekholdt, S Matthijs / Boerwinkle, Eric / Braund, Peter S / Brown, Morris J / Burnett, Mary Susan / Buysschaert, Ian / Anonymous3291162 / Carlquist, John F / Chen, Li / Cichon, Sven / Codd, Veryan / Davies, Robert W / Dedoussis, George / Dehghan, Abbas / Demissie, Serkalem / Devaney, Joseph M / Diemert, Patrick / Do, Ron / Doering, Angela / Eifert, Sandra / Mokhtari, Nour Eddine El / Ellis, Stephen G / Elosua, Roberto / Engert, James C / Epstein, Stephen E / de Faire, Ulf / Fischer, Marcus / Folsom, Aaron R / Freyer, Jennifer / Gigante, Bruna / Girelli, Domenico / Gretarsdottir, Solveig / Gudnason, Vilmundur / Gulcher, Jeffrey R / Halperin, Eran / Hammond, Naomi / Hazen, Stanley L / Hofman, Albert / Horne, Benjamin D / Illig, Thomas / Iribarren, Carlos / Jones, Gregory T / Jukema, J Wouter / Kaiser, Michael A / Kaplan, Lee M / Kastelein, John J P / Khaw, Kay-Tee / Knowles, Joshua W / Kolovou, Genovefa / Kong, Augustine / Laaksonen, Reijo / Lambrechts, Diether / Leander, Karin / Lettre, Guillaume / Li, Mingyao / Lieb, Wolfgang / Loley, Christina / Lotery, Andrew J / Mannucci, Pier M / Maouche, Seraya / Martinelli, Nicola / McKeown, Pascal P / Meisinger, Christa / Meitinger, Thomas / Melander, Olle / Merlini, Pier Angelica / Mooser, Vincent / Morgan, Thomas / Mühleisen, Thomas W / Muhlestein, Joseph B / Münzel, Thomas / Musunuru, Kiran / Nahrstaedt, Janja / Nelson, Christopher P / Nöthen, Markus M / Olivieri, Oliviero / Patel, Riyaz S / Patterson, Chris C / Peters, Annette / Peyvandi, Flora / Qu, Liming / Quyyumi, Arshed A / Rader, Daniel J / Rallidis, Loukianos S / Rice, Catherine / Rosendaal, Frits R / Rubin, Diana / Salomaa, Veikko / Sampietro, M Lourdes / Sandhu, Manj S / Schadt, Eric / Schäfer, Arne / Schillert, Arne / Schreiber, Stefan / Schrezenmeir, Jürgen / Schwartz, Stephen M / Siscovick, David S / Sivananthan, Mohan / Sivapalaratnam, Suthesh / Smith, Albert / Smith, Tamara B / Snoep, Jaapjan D / Soranzo, Nicole / Spertus, John A / Stark, Klaus / Stirrups, Kathy / Stoll, Monika / Tang, W H Wilson / Tennstedt, Stephanie / Thorgeirsson, Gudmundur / Thorleifsson, Gudmar / Tomaszewski, Maciej / Uitterlinden, Andre G / van Rij, Andre M / Voight, Benjamin F / Wareham, Nick J / Wells, George A / Wichmann, H-Erich / Wild, Philipp S / Willenborg, Christina / Witteman, Jaqueline C M / Wright, Benjamin J / Ye, Shu / Zeller, Tanja / Ziegler, Andreas / Cambien, Francois / Goodall, Alison H / Cupples, L Adrienne / Quertermous, Thomas / März, Winfried / Hengstenberg, Christian / Blankenberg, Stefan / Ouwehand, Willem H / Hall, Alistair S / Deloukas, Panos / Thompson, John R / Stefansson, Kari / Roberts, Robert / Thorsteinsdottir, Unnur / O'Donnell, Christopher J / McPherson, Ruth / Erdmann, Jeanette / Anonymous3301162 / Samani, Nilesh J. ·Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. ·Nat Genet · Pubmed #21378990.

ABSTRACT: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

17 Article Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies. 2010

Assimes, Themistocles L / Hólm, Hilma / Kathiresan, Sekar / Reilly, Muredach P / Thorleifsson, Gudmar / Voight, Benjamin F / Erdmann, Jeanette / Willenborg, Christina / Vaidya, Dhananjay / Xie, Changchun / Patterson, Chris C / Morgan, Thomas M / Burnett, Mary Susan / Li, Mingyao / Hlatky, Mark A / Knowles, Joshua W / Thompson, John R / Absher, Devin / Iribarren, Carlos / Go, Alan / Fortmann, Stephen P / Sidney, Stephen / Risch, Neil / Tang, Hua / Myers, Richard M / Berger, Klaus / Stoll, Monika / Shah, Svati H / Thorgeirsson, Gudmundur / Andersen, Karl / Havulinna, Aki S / Herrera, J Enrique / Faraday, Nauder / Kim, Yoonhee / Kral, Brian G / Mathias, Rasika A / Ruczinski, Ingo / Suktitipat, Bhoom / Wilson, Alexander F / Yanek, Lisa R / Becker, Lewis C / Linsel-Nitschke, Patrick / Lieb, Wolfgang / König, Inke R / Hengstenberg, Christian / Fischer, Marcus / Stark, Klaus / Reinhard, Wibke / Winogradow, Janina / Grassl, Martina / Grosshennig, Anika / Preuss, Michael / Schreiber, Stefan / Wichmann, H-Erich / Meisinger, Christa / Yee, Jean / Friedlander, Yechiel / Do, Ron / Meigs, James B / Williams, Gordon / Nathan, David M / MacRae, Calum A / Qu, Liming / Wilensky, Robert L / Matthai, William H / Qasim, Atif N / Hakonarson, Hakon / Pichard, Augusto D / Kent, Kenneth M / Satler, Lowell / Lindsay, Joseph M / Waksman, Ron / Knouff, Christopher W / Waterworth, Dawn M / Walker, Max C / Mooser, Vincent E / Marrugat, Jaume / Lucas, Gavin / Subirana, Isaac / Sala, Joan / Ramos, Rafael / Martinelli, Nicola / Olivieri, Oliviero / Trabetti, Elisabetta / Malerba, Giovanni / Pignatti, Pier Franco / Guiducci, Candace / Mirel, Daniel / Parkin, Melissa / Hirschhorn, Joel N / Asselta, Rosanna / Duga, Stefano / Musunuru, Kiran / Daly, Mark J / Purcell, Shaun / Eifert, Sandra / Braund, Peter S / Wright, Benjamin J / Balmforth, Anthony J / Ball, Stephen G / Anonymous2921162 / Anonymous2931162 / Anonymous2941162 / Ouwehand, Willem H / Deloukas, Panos / Scholz, Michael / Cambien, Francois / Huge, Andreas / Scheffold, Thomas / Salomaa, Veikko / Girelli, Domenico / Granger, Christopher B / Peltonen, Leena / McKeown, Pascal P / Altshuler, David / Melander, Olle / Devaney, Joseph M / Epstein, Stephen E / Rader, Daniel J / Elosua, Roberto / Engert, James C / Anand, Sonia S / Hall, Alistair S / Ziegler, Andreas / O'Donnell, Christopher J / Spertus, John A / Siscovick, David / Schwartz, Stephen M / Becker, Diane / Thorsteinsdottir, Unnur / Stefansson, Kari / Schunkert, Heribert / Samani, Nilesh J / Quertermous, Thomas. ·Department of Medicine, Stanford University School of Medicine, Stanford, California 94304-1334, USA. tassimes@stanford.edu ·J Am Coll Cardiol · Pubmed #20933357.

ABSTRACT: OBJECTIVES: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). BACKGROUND: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. METHODS: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. RESULTS: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. CONCLUSIONS: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

18 Article Biological, clinical and population relevance of 95 loci for blood lipids. 2010

Teslovich, Tanya M / Musunuru, Kiran / Smith, Albert V / Edmondson, Andrew C / Stylianou, Ioannis M / Koseki, Masahiro / Pirruccello, James P / Ripatti, Samuli / Chasman, Daniel I / Willer, Cristen J / Johansen, Christopher T / Fouchier, Sigrid W / Isaacs, Aaron / Peloso, Gina M / Barbalic, Maja / Ricketts, Sally L / Bis, Joshua C / Aulchenko, Yurii S / Thorleifsson, Gudmar / Feitosa, Mary F / Chambers, John / Orho-Melander, Marju / Melander, Olle / Johnson, Toby / Li, Xiaohui / Guo, Xiuqing / Li, Mingyao / Shin Cho, Yoon / Jin Go, Min / Jin Kim, Young / Lee, Jong-Young / Park, Taesung / Kim, Kyunga / Sim, Xueling / Twee-Hee Ong, Rick / Croteau-Chonka, Damien C / Lange, Leslie A / Smith, Joshua D / Song, Kijoung / Hua Zhao, Jing / Yuan, Xin / Luan, Jian'an / Lamina, Claudia / Ziegler, Andreas / Zhang, Weihua / Zee, Robert Y L / Wright, Alan F / Witteman, Jacqueline C M / Wilson, James F / Willemsen, Gonneke / Wichmann, H-Erich / Whitfield, John B / Waterworth, Dawn M / Wareham, Nicholas J / Waeber, Gérard / Vollenweider, Peter / Voight, Benjamin F / Vitart, Veronique / Uitterlinden, Andre G / Uda, Manuela / Tuomilehto, Jaakko / Thompson, John R / Tanaka, Toshiko / Surakka, Ida / Stringham, Heather M / Spector, Tim D / Soranzo, Nicole / Smit, Johannes H / Sinisalo, Juha / Silander, Kaisa / Sijbrands, Eric J G / Scuteri, Angelo / Scott, James / Schlessinger, David / Sanna, Serena / Salomaa, Veikko / Saharinen, Juha / Sabatti, Chiara / Ruokonen, Aimo / Rudan, Igor / Rose, Lynda M / Roberts, Robert / Rieder, Mark / Psaty, Bruce M / Pramstaller, Peter P / Pichler, Irene / Perola, Markus / Penninx, Brenda W J H / Pedersen, Nancy L / Pattaro, Cristian / Parker, Alex N / Pare, Guillaume / Oostra, Ben A / O'Donnell, Christopher J / Nieminen, Markku S / Nickerson, Deborah A / Montgomery, Grant W / Meitinger, Thomas / McPherson, Ruth / McCarthy, Mark I / McArdle, Wendy / Masson, David / Martin, Nicholas G / Marroni, Fabio / Mangino, Massimo / Magnusson, Patrik K E / Lucas, Gavin / Luben, Robert / Loos, Ruth J F / Lokki, Marja-Liisa / Lettre, Guillaume / Langenberg, Claudia / Launer, Lenore J / Lakatta, Edward G / Laaksonen, Reijo / Kyvik, Kirsten O / Kronenberg, Florian / König, Inke R / Khaw, Kay-Tee / Kaprio, Jaakko / Kaplan, Lee M / Johansson, Asa / Jarvelin, Marjo-Riitta / Janssens, A Cecile J W / Ingelsson, Erik / Igl, Wilmar / Kees Hovingh, G / Hottenga, Jouke-Jan / Hofman, Albert / Hicks, Andrew A / Hengstenberg, Christian / Heid, Iris M / Hayward, Caroline / Havulinna, Aki S / Hastie, Nicholas D / Harris, Tamara B / Haritunians, Talin / Hall, Alistair S / Gyllensten, Ulf / Guiducci, Candace / Groop, Leif C / Gonzalez, Elena / Gieger, Christian / Freimer, Nelson B / Ferrucci, Luigi / Erdmann, Jeanette / Elliott, Paul / Ejebe, Kenechi G / Döring, Angela / Dominiczak, Anna F / Demissie, Serkalem / Deloukas, Panagiotis / de Geus, Eco J C / de Faire, Ulf / Crawford, Gabriel / Collins, Francis S / Chen, Yii-der I / Caulfield, Mark J / Campbell, Harry / Burtt, Noel P / Bonnycastle, Lori L / Boomsma, Dorret I / Boekholdt, S Matthijs / Bergman, Richard N / Barroso, Inês / Bandinelli, Stefania / Ballantyne, Christie M / Assimes, Themistocles L / Quertermous, Thomas / Altshuler, David / Seielstad, Mark / Wong, Tien Y / Tai, E-Shyong / Feranil, Alan B / Kuzawa, Christopher W / Adair, Linda S / Taylor, Herman A / Borecki, Ingrid B / Gabriel, Stacey B / Wilson, James G / Holm, Hilma / Thorsteinsdottir, Unnur / Gudnason, Vilmundur / Krauss, Ronald M / Mohlke, Karen L / Ordovas, Jose M / Munroe, Patricia B / Kooner, Jaspal S / Tall, Alan R / Hegele, Robert A / Kastelein, John J P / Schadt, Eric E / Rotter, Jerome I / Boerwinkle, Eric / Strachan, David P / Mooser, Vincent / Stefansson, Kari / Reilly, Muredach P / Samani, Nilesh J / Schunkert, Heribert / Cupples, L Adrienne / Sandhu, Manjinder S / Ridker, Paul M / Rader, Daniel J / van Duijn, Cornelia M / Peltonen, Leena / Abecasis, Gonçalo R / Boehnke, Michael / Kathiresan, Sekar. ·Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. ·Nature · Pubmed #20686565.

ABSTRACT: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

19 Article New common variants affecting susceptibility to basal cell carcinoma. 2009

Stacey, Simon N / Sulem, Patrick / Masson, Gisli / Gudjonsson, Sigurjon A / Thorleifsson, Gudmar / Jakobsdottir, Margret / Sigurdsson, Asgeir / Gudbjartsson, Daniel F / Sigurgeirsson, Bardur / Benediktsdottir, Kristrun R / Thorisdottir, Kristin / Ragnarsson, Rafn / Scherer, Dominique / Hemminki, Kari / Rudnai, Peter / Gurzau, Eugene / Koppova, Kvetoslava / Botella-Estrada, Rafael / Soriano, Virtudes / Juberias, Pablo / Saez, Berta / Gilaberte, Yolanda / Fuentelsaz, Victoria / Corredera, Cristina / Grasa, Matilde / Höiom, Veronica / Lindblom, Annika / Bonenkamp, Johannes J / van Rossum, Michelle M / Aben, Katja K H / de Vries, Esther / Santinami, Mario / Di Mauro, Maria G / Maurichi, Andrea / Wendt, Judith / Hochleitner, Pia / Pehamberger, Hubert / Gudmundsson, Julius / Magnusdottir, Droplaug N / Gretarsdottir, Solveig / Holm, Hilma / Steinthorsdottir, Valgerdur / Frigge, Michael L / Blondal, Thorarinn / Saemundsdottir, Jona / Bjarnason, Hjördis / Kristjansson, Kristleifur / Bjornsdottir, Gyda / Okamoto, Ichiro / Rivoltini, Licia / Rodolfo, Monica / Kiemeney, Lambertus A / Hansson, Johan / Nagore, Eduardo / Mayordomo, José I / Kumar, Rajiv / Karagas, Margaret R / Nelson, Heather H / Gulcher, Jeffrey R / Rafnar, Thorunn / Thorsteinsdottir, Unnur / Olafsson, Jon H / Kong, Augustine / Stefansson, Kari. ·deCODE genetics, Reykjavik, Iceland. simon.stacey@decode.is ·Nat Genet · Pubmed #19578363.

ABSTRACT: In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.