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Coronary Artery Disease: HELP
Articles by Daniel J. Rader
Based on 62 articles published since 2008
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Between 2008 and 2019, Dan Rader wrote the following 62 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Intracoronary Imaging, Reverse Cholesterol Transport, and Transcriptomics: Precision Medicine in CAD? 2017

Chhatriwalla, Adnan K / Rader, Daniel J. ·Division of Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri; Department of Medicine, University of Missouri-Kansas City, Kansas City, Missouri. Electronic address: achhatriwalla@saint-lukes.org. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ·J Am Coll Cardiol · Pubmed #28183507.

ABSTRACT: -- No abstract --

2 Editorial Reducing the burden of disease and death from familial hypercholesterolemia: a call to action. 2014

Knowles, Joshua W / O'Brien, Emily C / Greendale, Karen / Wilemon, Katherine / Genest, Jacques / Sperling, Laurence S / Neal, William A / Rader, Daniel J / Khoury, Muin J. ·Stanford University School of Medicine and Cardiovascular Institute, Stanford, CA; The FH Foundation, South Pasadena, CA. · Duke Clinical Research Institute, Durham, NC. Electronic address: emily.obrien@duke.edu. · The FH Foundation, South Pasadena, CA. · McGill University, Montreal, Canada. · Emory University School of Medicine, Atlanta, GA. · West Virginia University, Morgantown, WV. · University of Pennsylvania, Philadelphia, PA. · Office of Public Health Genomics, Centers for Disease Control & Prevention, Atlanta, GA. ·Am Heart J · Pubmed #25458642.

ABSTRACT: Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a "call to action" to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition.

3 Review Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. 2016

Javaheri, Ali / Molina, Maria / Zamani, Payman / Rodrigues, Amrith / Novak, Eric / Chambers, Susan / Stutman, Patricia / Maslanek, Wilhelmina / Williams, Mary / Lilly, Scott M / Heeger, Peter / Sayegh, Mohamed H / Chandraker, Anil / Briscoe, David M / Daly, Kevin P / Starling, Randall / Ikle, David / Christie, Jason / Rame, J Eduardo / Goldberg, Lee R / Billheimer, Jeffrey / Rader, Daniel J. ·Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: ali.javaheri@wustl.edu. · Division of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA. · Division of Cardiology, Ohio State University, Columbus, Ohio, USA. · Icahn School of Medicine at Mount Sinai, New York, New York. · Brigham & Women׳s Hospital, Harvard University, Boston, Massachusetts, USA; Department of Medicine and Immunology, American University of Beirut, Beirut, Lebanon. · Brigham & Women׳s Hospital, Harvard University, Boston, Massachusetts, USA. · Children's Hospital Boston, Boston, Massachusetts, USA. · Cleveland Clinic, Cleveland, Ohio, USA. · Department of Biostatistics, Rho Federal Systems Division, Rho, Inc., Chapel Hill, North Carolina, USA. ·J Heart Lung Transplant · Pubmed #27498384.

ABSTRACT: BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS: We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. RESULTS: Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = -0.59, p = 0.02, R CONCLUSION: Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.

4 Review Targeting ApoC-III to Reduce Coronary Disease Risk. 2016

Khetarpal, Sumeet A / Qamar, Arman / Millar, John S / Rader, Daniel J. ·Perelman School of Medicine, University of Pennsylvania, 11-125 SCTR, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA. · Perelman School of Medicine, University of Pennsylvania, 11-125 SCTR, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA. rader@mail.med.upenn.edu. ·Curr Atheroscler Rep · Pubmed #27443326.

ABSTRACT: Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk.

5 Review Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics. 2016

Bauer, Robert C / Khetarpal, Sumeet A / Hand, Nicholas J / Rader, Daniel J. ·Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA. · Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5159, USA. Electronic address: rader@mail.med.upenn.edu. ·Trends Mol Med · Pubmed #26988439.

ABSTRACT: Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions.

6 Review From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease. 2016

Nurnberg, Sylvia T / Zhang, Hanrui / Hand, Nicholas J / Bauer, Robert C / Saleheen, Danish / Reilly, Muredach P / Rader, Daniel J. ·From the Division of Translational Medicine and Human Genetics, Department of Medicine (S.T.N., R.C.B., D.J.R.), Penn Cardiovascular Institute, Department of Medicine (H.Z., M.P.R., D.J.R.), Department of Genetics (N.J.H., D.J.R.), and Department of Biostatistics and Epidemiology (D.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. · From the Division of Translational Medicine and Human Genetics, Department of Medicine (S.T.N., R.C.B., D.J.R.), Penn Cardiovascular Institute, Department of Medicine (H.Z., M.P.R., D.J.R.), Department of Genetics (N.J.H., D.J.R.), and Department of Biostatistics and Epidemiology (D.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. mpr2144@cumc.columbia.edu rader@upenn.edu. ·Circ Res · Pubmed #26892960.

ABSTRACT: Genome-wide association studies have provided a rich collection of ≈ 58 coronary artery disease (CAD) loci that suggest the existence of previously unsuspected new biology relevant to atherosclerosis. However, these studies only identify genomic loci associated with CAD, and many questions remain even after a genomic locus is definitively implicated, including the nature of the causal variant(s) and the causal gene(s), as well as the directionality of effect. There are several tools that can be used for investigation of the functional genomics of these loci, and progress has been made on a limited number of novel CAD loci. New biology regarding atherosclerosis and CAD will be learned through the functional genomics of these loci, and the hope is that at least some of these new pathways relevant to CAD pathogenesis will yield new therapeutic targets for the prevention and treatment of CAD.

7 Review Lipoproteins as biomarkers and therapeutic targets in the setting of acute coronary syndrome. 2014

Rosenson, Robert S / Brewer, H Bryan / Rader, Daniel J. ·From the Department of Medicine (Cardiology), Icahn School of Medicine at Mount Sinai, New York, NY (R.S.R.) · Cardiovascular Research Institute, Medstar Research Institute, Washington Hospital Center, DC (H.B.B.) · and Departments of Medicine and Genetics and Cardiovascular Institute, Perelman School of Medicine of the University of Pennsylvania, Philadelphia (D.J.R.). ·Circ Res · Pubmed #24902972.

ABSTRACT: The period following an acute coronary syndrome (ACS) represents a critical time frame with a high risk for recurrent events and death. The pathogenesis of this increase in clinical cardiovascular disease events after ACS is complex, with molecular mechanisms including increased thrombosis and inflammation. Dyslipoproteinemia is common in patients with ACS and predictive of recurrent cardiovascular disease events after presentation with an ACS event. Although randomized clinical trials have provided fairly convincing evidence that high-dose statins reduce the risk of recurrent cardiovascular events after ACS, there remain questions about how aggressively to reduce low-density lipoprotein cholesterol levels in ACS. Furthermore, no other lipid-related interventions have yet been proven to be effective in reducing major cardiovascular events after ACS. Here, we review the relationship of lipoproteins as biomarkers to cardiovascular risk after ACS, the evidence for lipid-targeted interventions, and the potential for novel therapeutic approaches in this arena.

8 Review New therapies for coronary artery disease: genetics provides a blueprint. 2014

Rader, Daniel J. ·Department of Medicine and Department of Genetics, Cardiovascular Institute, and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Sci Transl Med · Pubmed #24898745.

ABSTRACT: The development of new therapies for coronary artery disease (CAD) poses a substantial challenge, and several recent approaches have failed for lack of efficacy. Human genetics has the potential to identify new targets for which the likelihood of therapeutic success is considerably greater. The intense focus on the genetics of CAD will revitalize the field and lead to future therapies for this common disease.

9 Review Genetics of lipid traits and relationship to coronary artery disease. 2013

Keenan, Tanya E / Rader, Daniel J. ·Perelman School of Medicine at the University of Pennsylvania, 8044 Maloney Building, 3400 Spruce St, Philadelphia, PA 19104, USA. keenant@mail.med.upenn.edu ·Curr Cardiol Rep · Pubmed #23881580.

ABSTRACT: Despite the critical importance of plasma lipoproteins in the development of atherosclerosis, varying degrees of evidence surround the causal associations of lipoproteins with coronary artery disease (CAD). These causal contributions can be assessed by employing genetic variants as unbiased proxies for lipid levels. A relatively large number of low-density lipoprotein cholesterol (LDL-C) variants strongly associate with CAD, confirming the causal impact of this lipoprotein on atherosclerosis. Although not as firmly established, genetic evidence supporting a causal role of triglycerides (TG) in CAD is growing. Conversely, high-density lipoprotein cholesterol (HDL-C) variants not associated with LDL-C or TG have not yet been shown to be convincingly associated with CAD, raising questions about the causality of HDL-C in atherosclerosis. Finally, genetic variants at the LPA locus associated with lipoprotein(a) [Lp(a)] are decisively linked to CAD, indicating a causal role for Lp(a). Translational investigation of CAD-associated lipid variants may identify novel regulatory pathways with therapeutic potential to alter CAD risk.

10 Review Effect of interleukin 1β inhibition in cardiovascular disease. 2012

Qamar, Arman / Rader, Daniel J. ·Cardiovascular Institute, Institute for Translational Medicine and Therapeutics, and Department of Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Curr Opin Lipidol · Pubmed #23069985.

ABSTRACT: PURPOSE OF REVIEW: Atherosclerosis is greatly influenced by inflammatory mediators at all phases. Recent studies have suggested a causal role of one such mediator, interleukin 1β (IL-1β), in the development of atherosclerotic vascular disease. This review highlights recent investigation of the role of IL-1β in atherosclerosis and the potential of its inhibition as a promising therapeutic strategy for the treatment of atherosclerotic vascular disease. RECENT FINDINGS: Studies in animals have generally shown decreased atherosclerotic plaque burden in atherosclerosis-prone mice deficient in IL-1β and increased plaque in mice exposed to excess IL-1β. In humans, IL-1β was found in greater concentrations in atherosclerotic human coronary arteries compared with normal coronary arteries. Preclinical and clinical studies of IL-1β inhibition have shown efficacy in the treatment of several inflammatory disorders, suggesting that IL-1β may be a novel therapeutic target for anti-inflammatory therapy in atherosclerosis, such as coronary artery disease (CAD). SUMMARY: IL-1β inhibition offers an interesting and biology-based opportunity to test the potential beneficial effects of an anti-inflammatory therapeutic strategy in patients with CAD. A large clinical trial evaluating the impact of IL-1β inhibition in CAD is ongoing and will be an important test of the inflammation hypothesis in CAD.

11 Review Genetic basis of atherosclerosis: insights from mice and humans. 2012

Stylianou, Ioannis M / Bauer, Robert C / Reilly, Muredach P / Rader, Daniel J. ·Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 654 BRBII/III Labs, 421 Curie Boulevard, Philadelphia, Pennsylvania, 19104-6160, USA. ·Circ Res · Pubmed #22267839.

ABSTRACT: Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have, in part, been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease. Here, we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human coronary artery disease. Furthermore, we discuss in greater detail some of these novel human coronary artery disease loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candidates for new therapeutic approaches.

12 Review The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels. 2011

Mehta, Nehal N / Li, Mingyao / William, Dilusha / Khera, Amit V / DerOhannessian, Stephanie / Qu, Liming / Ferguson, Jane F / McLaughlin, Catherine / Shaikh, Lalarukh Haris / Shah, Rhia / Patel, Parth N / Bradfield, Jonathan P / He, Jing / Stylianou, Ioannis M / Hakonarson, Hakon / Rader, Daniel J / Reilly, Muredach P. ·Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Penn Tower, 6th Floor, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA. nehal.mehta@uphs.upenn.edu ·Eur Heart J · Pubmed #21415067.

ABSTRACT: AIMS: Two single-nucleotide polymorphisms (SNPs), rs1746048 and rs501120, from genome wide association studies of coronary artery disease (CAD) map to chromosome 10q11 ∼80 kb downstream of chemokine CXCL12. Therefore, we examined the relationship between these two SNPs and plasma CXCL12 levels. METHODS AND RESULTS: We tested the association of two SNPs with plasma CXCL12 levels in a two-stage study (n= 2939): first in PennCath (n= 1182), a Caucasian, angiographic CAD case-control study, and second in PennCAC (n= 1757), a community-based study of CAD risk factors. Plasma CXCL12 levels increased with age and did not vary by gender. There was no linkage disequilibrium between these two SNPs and SNPs within CXCL12 gene. However, CAD risk alleles at rs1746048 (C allele, P= 0.034; CC 2.33 ± 0.49, CT 2.27 ± 0.46, and TT 2.21 ± 0.52 ng/mL) and rs501120 (T allele, P= 0.041; TT 2.34 ± 0.49, CT 2.28 ± 0.46, and CC 2.23 ± 0.53 ng/mL) were associated with higher plasma levels of CXCL12 in age and gender adjusted models. In Stage 2, we confirmed this association (rs501120, T allele, P= 0.007), and meta-analysis strengthened this finding (n= 2939, P= 6.0 × 10(-4)). Finally, in exploratory analysis, the rs1746048 risk allele tended to have higher transcript levels of CXCL12 in human natural killer cells and the liver. CONCLUSION: Coronary artery disease risk alleles downstream of CXCL12 are associated with plasma protein levels of CXCL12 and appear to be related to CXCL12 transcript levels in two human cell lines. This implicates CXCL12 as potentially causal and supports CXCL12 as a potential therapeutic target for CAD.

13 Review CXCL12: a new player in coronary disease identified through human genetics. 2010

Farouk, Samira S / Rader, Daniel J / Reilly, Muredach P / Mehta, Nehal N. ·Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. ·Trends Cardiovasc Med · Pubmed #22137643.

ABSTRACT: Genome-wide association studies (GWAS) of more than 100,000 people have revealed novel loci associated with coronary artery disease and myocardial infarction that present exciting opportunities to discover novel disease pathways. One such recently identified locus is on chromosome 10q11, near the gene for the chemokine CXCL12, which has been implicated in cardiovascular disease in both mouse and human studies. These GWAS demonstrate that CXCL12 may emerge as a potential therapeutic target for atherosclerosis and thrombosis.

14 Review Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. 2008

deGoma, Emil M / deGoma, Rolando L / Rader, Daniel J. ·Department of Cardiology, Stanford University Hospital, Stanford, California 94305, USA. edegoma@stanford.edu ·J Am Coll Cardiol · Pubmed #18534265.

ABSTRACT: A number of therapeutic strategies targeting high-density lipoprotein (HDL) cholesterol and reverse cholesterol transport are being developed to halt the progression of atherosclerosis or even induce regression. However, circulating HDL cholesterol levels alone represent an inadequate measure of therapeutic efficacy. Evaluation of the potential effects of HDL-targeted interventions on atherosclerosis requires reliable assays of HDL function and surrogate markers of efficacy. Promotion of macrophage cholesterol efflux and reverse cholesterol transport is thought to be one of the most important mechanisms by which HDL protects against atherosclerosis, and methods to assess this pathway in vivo are being developed. Indexes of monocyte chemotaxis, endothelial inflammation, oxidation, nitric oxide production, and thrombosis reveal other dimensions of HDL functionality. Robust, reproducible assays that can be performed widely are needed to move this field forward and permit effective assessment of the therapeutic potential of HDL-targeted therapies.

15 Clinical Trial Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. 2017

Dewey, Frederick E / Gusarova, Viktoria / Dunbar, Richard L / O'Dushlaine, Colm / Schurmann, Claudia / Gottesman, Omri / McCarthy, Shane / Van Hout, Cristopher V / Bruse, Shannon / Dansky, Hayes M / Leader, Joseph B / Murray, Michael F / Ritchie, Marylyn D / Kirchner, H Lester / Habegger, Lukas / Lopez, Alex / Penn, John / Zhao, An / Shao, Weiping / Stahl, Neil / Murphy, Andrew J / Hamon, Sara / Bouzelmat, Aurelie / Zhang, Rick / Shumel, Brad / Pordy, Robert / Gipe, Daniel / Herman, Gary A / Sheu, Wayne H H / Lee, I-Te / Liang, Kae-Woei / Guo, Xiuqing / Rotter, Jerome I / Chen, Yii-Der I / Kraus, William E / Shah, Svati H / Damrauer, Scott / Small, Aeron / Rader, Daniel J / Wulff, Anders Berg / Nordestgaard, Børge G / Tybjærg-Hansen, Anne / van den Hoek, Anita M / Princen, Hans M G / Ledbetter, David H / Carey, David J / Overton, John D / Reid, Jeffrey G / Sasiela, William J / Banerjee, Poulabi / Shuldiner, Alan R / Borecki, Ingrid B / Teslovich, Tanya M / Yancopoulos, George D / Mellis, Scott J / Gromada, Jesper / Baras, Aris. ·From Regeneron Genetics Center (F.E.D., C.O., C.S., O.G., S.M., C.V.V.H., S.B., L.H., A.L., J.P., N.S., A.J.M., J.D.O., J.G.R., A.R.S., I.B.B., T.M.T., G.D.Y., S.J.M., A. Baras) and Regeneron Pharmaceuticals (V.G., H.M.D., A.Z., W.S., N.S., A.J.M., S.H., A. Bouzelmat, R.Z., B.S., R.P., D.G., G.A.H., W.J.S., P.B., G.D.Y., S.J.M., J.G.) Tarrytown, NY · the Department of Medicine, Division of Translational Medicine and Human Genetics (R.L.D.), and Departments of Surgery (S.D.) and Genetics and Medicine (A.S., D.J.R.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, and Geisinger Health System, Danville (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.) - both in Pennsylvania · the Division of Endocrinology and Metabolism, Department of Internal Medicine (W.H.H.S., I.-T.L.) and Cardiovascular Center (K.-W.L.), Taichung Veterans General Hospital, Institute of Medical Technology, National Chung-Hsing University (W.H.H.S.), School of Medicine, Chung Shan Medical University (I.-T.L.), and the Department of Medicine, China Medical University (K.-W.L.), Taichung, and School of Medicine, National Yang-Ming University (W.H.H.S., I.-T.L., K.-W.L.), and School of Medicine, National Defense Medical Center (W.H.H.S.), Taipei - all in Taiwan · Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA (X.G., J.I.R., Y.-D.I.C.) · the Division of Cardiology, Department of Medicine, Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC (W.E.K., S.H.S.) · the Department of Clinical Biochemistry, Rigshospitalet (A.B.W., B.G.N., A.T.-H.), the Copenhagen General Population Study (B.G.N., A.T.-H.) and Department of Clinical Biochemistry (B.G.N.), Herlev and Gentofte Hospital, and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, and Faculty of Health and Medical Sciences, University of Copenhagen (B.G.N., A.T.-H.) - all in Copenhagen · and TNO Metabolic Health Research, Gaubius Laboratory, Leiden, the Netherlands (A.M.H., H.M.G.P.). ·N Engl J Med · Pubmed #28538136.

ABSTRACT: BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

16 Clinical Trial Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial. 2015

Nicholls, Stephen J / Lincoff, A Michael / Barter, Philip J / Brewer, H Bryan / Fox, Keith A A / Gibson, C Michael / Grainger, Christopher / Menon, Venugopal / Montalescot, Gilles / Rader, Daniel / Tall, Alan R / McErlean, Ellen / Riesmeyer, Jeffrey / Vangerow, Burkhard / Ruotolo, Giacomo / Weerakkody, Govinda J / Nissen, Steven E. ·South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia. · Cleveland Clinic Coordinating Center for Clinical Research and Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH. · University of New South Wales, Sydney, Australia. · Medstar Research Institute, Hyattsville, MD. · University of Edinburgh, Edinburgh, Scotland. · Harvard Medical School, Boston, MA. · Duke Clinical Research Institute, Durham, NC. · Pitie-Salpetriere University Hospital, Paris, France. · University of Pennsylvania, Philadelphia, PA. · Columbia University, New York City, NY. · Eli Lilly and Company, Indianapolis, IN. ·Am Heart J · Pubmed #26678626.

ABSTRACT: BACKGROUND: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease. STUDY DESIGN: ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years. CONCLUSIONS: ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease.

17 Article Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci. 2018

Liu, Boxiang / Pjanic, Milos / Wang, Ting / Nguyen, Trieu / Gloudemans, Michael / Rao, Abhiram / Castano, Victor G / Nurnberg, Sylvia / Rader, Daniel J / Elwyn, Susannah / Ingelsson, Erik / Montgomery, Stephen B / Miller, Clint L / Quertermous, Thomas. ·Department of Biology, School of Humanities and Sciences, Stanford University, Stanford, CA 94305, USA; Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. · Biomedical Informatics Training Program, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. · Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. · Center for Public Health Genomics, Department of Public Health Sciences, Biochemistry and Genetics, and Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA. · Cardiovascular Institute, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: tomq1@stanford.edu. ·Am J Hum Genet · Pubmed #30146127.

ABSTRACT: Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWASs) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMCs) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMCs. We assessed the relevance of HCASMCs to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that may modulate CAD risk through HCASMCs, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMCs, while other annotated genes may have multiple cell and tissue targets. Together, these results provide tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

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

Liu, Dajiang J / Peloso, Gina M / Yu, Haojie / Butterworth, Adam S / Wang, Xiao / Mahajan, Anubha / Saleheen, Danish / Emdin, Connor / Alam, Dewan / Alves, Alexessander Couto / Amouyel, Philippe / Di Angelantonio, Emanuele / Arveiler, Dominique / Assimes, Themistocles L / Auer, Paul L / Baber, Usman / Ballantyne, Christie M / Bang, Lia E / Benn, Marianne / Bis, Joshua C / Boehnke, Michael / Boerwinkle, Eric / Bork-Jensen, Jette / Bottinger, Erwin P / Brandslund, Ivan / Brown, Morris / Busonero, Fabio / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Y Eugene / Chen, Yii-Der Ida / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Connell, John M / Cucca, Francesco / Cupples, L Adrienne / Damrauer, Scott M / Davies, Gail / Deary, Ian J / Dedoussis, George / Denny, Joshua C / Dominiczak, Anna / Dubé, Marie-Pierre / Ebeling, Tapani / Eiriksdottir, Gudny / Esko, Tõnu / Farmaki, Aliki-Eleni / Feitosa, Mary F / Ferrario, Marco / Ferrieres, Jean / Ford, Ian / Fornage, Myriam / Franks, Paul W / Frayling, Timothy M / Frikke-Schmidt, Ruth / Fritsche, Lars G / Frossard, Philippe / Fuster, Valentin / Ganesh, Santhi K / Gao, Wei / Garcia, Melissa E / Gieger, Christian / Giulianini, Franco / Goodarzi, Mark O / Grallert, Harald / Grarup, Niels / Groop, Leif / Grove, Megan L / Gudnason, Vilmundur / Hansen, Torben / Harris, Tamara B / Hayward, Caroline / Hirschhorn, Joel N / Holmen, Oddgeir L / Huffman, Jennifer / Huo, Yong / Hveem, Kristian / Jabeen, Sehrish / Jackson, Anne U / Jakobsdottir, Johanna / Jarvelin, Marjo-Riitta / Jensen, Gorm B / Jørgensen, Marit E / Jukema, J Wouter / Justesen, Johanne M / Kamstrup, Pia R / Kanoni, Stavroula / Karpe, Fredrik / Kee, Frank / Khera, Amit V / Klarin, Derek / Koistinen, Heikki A / Kooner, Jaspal S / Kooperberg, Charles / Kuulasmaa, Kari / Kuusisto, Johanna / Laakso, Markku / Lakka, Timo / Langenberg, Claudia / Langsted, Anne / Launer, Lenore J / Lauritzen, Torsten / Liewald, David C M / Lin, Li An / Linneberg, Allan / Loos, Ruth J F / Lu, Yingchang / Lu, Xiangfeng / Mägi, Reedik / Malarstig, Anders / Manichaikul, Ani / Manning, Alisa K / Mäntyselkä, Pekka / Marouli, Eirini / Masca, Nicholas G D / Maschio, Andrea / Meigs, James B / Melander, Olle / Metspalu, Andres / Morris, Andrew P / Morrison, Alanna C / Mulas, Antonella / Müller-Nurasyid, Martina / Munroe, Patricia B / Neville, Matt J / Nielsen, Jonas B / Nielsen, Sune F / Nordestgaard, Børge G / Ordovas, Jose M / Mehran, Roxana / O'Donnell, Christoper J / Orho-Melander, Marju / Molony, Cliona M / Muntendam, Pieter / Padmanabhan, Sandosh / Palmer, Colin N A / Pasko, Dorota / Patel, Aniruddh P / Pedersen, Oluf / Perola, Markus / Peters, Annette / Pisinger, Charlotta / Pistis, Giorgio / Polasek, Ozren / Poulter, Neil / Psaty, Bruce M / Rader, Daniel J / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Reiner, Alex P / Renström, Frida / Rich, Stephen S / Ridker, Paul M / Rioux, John D / Robertson, Neil R / Roden, Dan M / Rotter, Jerome I / Rudan, Igor / Salomaa, Veikko / Samani, Nilesh J / Sanna, Serena / Sattar, Naveed / Schmidt, Ellen M / Scott, Robert A / Sever, Peter / Sevilla, Raquel S / Shaffer, Christian M / Sim, Xueling / Sivapalaratnam, Suthesh / Small, Kerrin S / Smith, Albert V / Smith, Blair H / Somayajula, Sangeetha / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Stirrups, Kathleen E / Stitziel, Nathan / Strauch, Konstantin / Stringham, Heather M / Surendran, Praveen / Tada, Hayato / Tall, Alan R / Tang, Hua / Tardif, Jean-Claude / Taylor, Kent D / Trompet, Stella / Tsao, Philip S / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / van Zuydam, Natalie R / Varbo, Anette / Varga, Tibor V / Virtamo, Jarmo / Waldenberger, Melanie / Wang, Nan / Wareham, Nick J / Warren, Helen R / Weeke, Peter E / Weinstock, Joshua / Wessel, Jennifer / Wilson, James G / Wilson, Peter W F / Xu, Ming / Yaghootkar, Hanieh / Young, Robin / Zeggini, Eleftheria / Zhang, He / Zheng, Neil S / Zhang, Weihua / Zhang, Yan / Zhou, Wei / Zhou, Yanhua / Zoledziewska, Magdalena / Anonymous7491224 / Anonymous7501224 / Anonymous7511224 / Anonymous7521224 / Anonymous7531224 / Howson, Joanna M M / Danesh, John / McCarthy, Mark I / Cowan, Chad A / Abecasis, Goncalo / Deloukas, Panos / Musunuru, Kiran / Willer, Cristen J / Kathiresan, Sekar. ·Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK. · Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · ICDDR, B, Dhaka, Bangladesh. · Imperial College London, London, UK. · Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France. · VA Palo Alto Health Care System, Palo Alto, California, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. · Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. · Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. · Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. · Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. · Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy. · The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK. · NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. · The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA. · Medical Department, Lillebaelt Hospital, Vejle, Denmark. · NHLBI Framingham Heart Study, Framingham, Massachusetts, USA. · Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. · Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. · Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Psychology, University of Edinburgh, Edinburgh, UK. · Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. · Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Montreal Heart Institute, Montreal, Quebec, Canada. · Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada. · Université de Montréal, Montreal, Quebec, Canada. · Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland. · The Icelandic Heart Association, Kopavogur, Iceland. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. · Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA. · Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK. · Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China. · National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA. · Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway. · St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. · Department of Cardiology, Peking University First Hospital, Beijing, China. · K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. · Department of Health Sciences, University of Iceland, Reykjavik, Iceland. · The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark. · Steno Diabetes Center, Gentofte, Denmark. · National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark. · Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. · The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. · UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Minerva Foundation Institute for Medical Research, Helsinki, Finland. · National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark. · Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark. · Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Research Center for Prevention and Health, Copenhagen, Denmark. · The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. · Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany. · DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA. · Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · G3 Pharmaceuticals, Lexington, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Institute of Molecular Medicine FIMM, University of Helsinki, Finland. · Faculty of Medicine, University of Split, Split, Croatia. · Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · International Centre for Circulatory Health, Imperial College London, London, UK. · Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA. · Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biobank Research, Umeå University, Umeå, Sweden. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. · Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Saw Swee Hock School of Public Health, National University of Singapore, Singapore. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK. · Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK. · Department of Haematology, University of Cambridge, Cambridge, UK. · Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA. · IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. · Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. · Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. · Dasman Diabetes Institute, Dasman, Kuwait. · Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. · Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia. · The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Atlanta VA Medical Center, Decatur, Georgia, USA. · Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA. · Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. · Yale College, Yale University, New Haven, Connecticut, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #29083408.

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

19 Article Paradoxical coronary artery disease in humans with hyperalphalipoproteinemia is associated with distinct differences in the high-density lipoprotein phosphosphingolipidome. 2017

Hancock-Cerutti, William / Lhomme, Marie / Dauteuille, Carolane / Lecocq, Sora / Chapman, M John / Rader, Daniel J / Kontush, Anatol / Cuchel, Marina. ·National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · ICANalytics, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France. · National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France. · Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · National Institute for Health and Medical Reserch (INSERM), Research Unit 1166 ICAN, Paris, France; University of Pierre and Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié Salpétrière, Paris, France; ICAN Analytics, ICAN Institute, Paris, France. Electronic address: anatol.kontush@upmc.fr. · Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mcuchel@mail.med.upenn.edu. ·J Clin Lipidol · Pubmed #28826666.

ABSTRACT: BACKGROUND: Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with risk of coronary artery disease (CAD) in epidemiologic studies. Despite this, the directionality of this relationship and the underlying biology behind it remain to be firmly established, especially at the extremes of HDL-C levels. OBJECTIVE: We investigated differences in the HDL phosphosphingolipidome in a rare population of subjects with premature CAD despite high HDL-C levels to gain insight into the association between the HDL lipidome and CAD disease status in this unusual phenotype. We sought to assess differences in HDL composition that are associated with CAD in subjects with HDL-C >90th percentile. We predicted that quantitative lipidomic analysis of HDL particles would reveal novel differences between CAD patients and healthy subjects with matched HDL-C levels. METHODS: We collected plasma samples from 25 subjects with HDL-C >90th percentile and clinically manifest CAD and healthy controls with HDL-C >90th percentile and without self-reported CAD. More than 140 individual HDL phospholipid and sphingolipid species were analyzed by LC/MS/MS. RESULTS: Significant reductions in HDL phosphatidylcholine (-2.41%, Q value = 0.025) and phosphatidylinositol (-10.7%, Q value = 0.047) content, as well as elevated sphingomyelin (+10.0%, Q value = 0.025) content, and sphingomyelin/phosphatidylcholine ratio (+12.8%, P value = .005) were associated with CAD status in subjects with high HDL-C. CONCLUSIONS: These differences may lay the groundwork for further analysis of the relationship between the HDL lipidome and disease states, as well as for the development of biomarkers of CAD status and HDL function.

20 Article Text mining applied to electronic cardiovascular procedure reports to identify patients with trileaflet aortic stenosis and coronary artery disease. 2017

Small, Aeron M / Kiss, Daniel H / Zlatsin, Yevgeny / Birtwell, David L / Williams, Heather / Guerraty, Marie A / Han, Yuchi / Anwaruddin, Saif / Holmes, John H / Chirinos, Julio A / Wilensky, Robert L / Giri, Jay / Rader, Daniel J. ·Department of Medicine and Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, PA, USA. · Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA. · Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Department of Medicine and Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, PA, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, PA, USA. Electronic address: rader@mail.med.upenn.edu. ·J Biomed Inform · Pubmed #28624641.

ABSTRACT: BACKGROUND: Interrogation of the electronic health record (EHR) using billing codes as a surrogate for diagnoses of interest has been widely used for clinical research. However, the accuracy of this methodology is variable, as it reflects billing codes rather than severity of disease, and depends on the disease and the accuracy of the coding practitioner. Systematic application of text mining to the EHR has had variable success for the detection of cardiovascular phenotypes. We hypothesize that the application of text mining algorithms to cardiovascular procedure reports may be a superior method to identify patients with cardiovascular conditions of interest. METHODS: We adapted the Oracle product Endeca, which utilizes text mining to identify terms of interest from a NoSQL-like database, for purposes of searching cardiovascular procedure reports and termed the tool "PennSeek". We imported 282,569 echocardiography reports representing 81,164 individuals and 27,205 cardiac catheterization reports representing 14,567 individuals from non-searchable databases into PennSeek. We then applied clinical criteria to these reports in PennSeek to identify patients with trileaflet aortic stenosis (TAS) and coronary artery disease (CAD). Accuracy of patient identification by text mining through PennSeek was compared with ICD-9 billing codes. RESULTS: Text mining identified 7115 patients with TAS and 9247 patients with CAD. ICD-9 codes identified 8272 patients with TAS and 6913 patients with CAD. 4346 patients with AS and 6024 patients with CAD were identified by both approaches. A randomly selected sample of 200-250 patients uniquely identified by text mining was compared with 200-250 patients uniquely identified by billing codes for both diseases. We demonstrate that text mining was superior, with a positive predictive value (PPV) of 0.95 compared to 0.53 by ICD-9 for TAS, and a PPV of 0.97 compared to 0.86 for CAD. CONCLUSION: These results highlight the superiority of text mining algorithms applied to electronic cardiovascular procedure reports in the identification of phenotypes of interest for cardiovascular research.

21 Article Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. 2017

Howson, Joanna M M / Zhao, Wei / Barnes, Daniel R / Ho, Weang-Kee / Young, Robin / Paul, Dirk S / Waite, Lindsay L / Freitag, Daniel F / Fauman, Eric B / Salfati, Elias L / Sun, Benjamin B / Eicher, John D / Johnson, Andrew D / Sheu, Wayne H H / Nielsen, Sune F / Lin, Wei-Yu / Surendran, Praveen / Malarstig, Anders / Wilk, Jemma B / Tybjærg-Hansen, Anne / Rasmussen, Katrine L / Kamstrup, Pia R / Deloukas, Panos / Erdmann, Jeanette / Kathiresan, Sekar / Samani, Nilesh J / Schunkert, Heribert / Watkins, Hugh / Anonymous2140907 / Do, Ron / Rader, Daniel J / Johnson, Julie A / Hazen, Stanley L / Quyyumi, Arshed A / Spertus, John A / Pepine, Carl J / Franceschini, Nora / Justice, Anne / Reiner, Alex P / Buyske, Steven / Hindorff, Lucia A / Carty, Cara L / North, Kari E / Kooperberg, Charles / Boerwinkle, Eric / Young, Kristin / Graff, Mariaelisa / Peters, Ulrike / Absher, Devin / Hsiung, Chao A / Lee, Wen-Jane / Taylor, Kent D / Chen, Ying-Hsiang / Lee, I-Te / Guo, Xiuqing / Chung, Ren-Hua / Hung, Yi-Jen / Rotter, Jerome I / Juang, Jyh-Ming J / Quertermous, Thomas / Wang, Tzung-Dau / Rasheed, Asif / Frossard, Philippe / Alam, Dewan S / Majumder, Abdulla Al Shafi / Di Angelantonio, Emanuele / Chowdhury, Rajiv / Anonymous2150907 / Chen, Yii-Der Ida / Nordestgaard, Børge G / Assimes, Themistocles L / Danesh, John / Butterworth, Adam S / Saleheen, Danish. ·MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Applied Mathematics, University of Nottingham Malaysia Campus, Semenyih, Malaysia. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. · Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA. · National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA. · NHLBI and Boston University's The Framingham Heart Study, Framingham, Massachusetts, USA. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · School of Medicine, National Yang-Ming University, Taipei, Taiwan. · College of Medicine, National Defense Medical Center, Taipei, Taiwan. · Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK. · Pfizer Worldwide Research and Development, Stockholm, Sweden. · Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Centre for Genomic Health, Queen Mary University of London, London, UK. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · University Heart Center Lübeck, Lübeck, Germany. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · University of Florida College of Pharmacy, Gainesville, Florida, USA. · Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA. · Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. · Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA. · Department of Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, Missouri, USA. · College of Medicine, University of Florida, Gainesville, Florida, USA. · Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA. · Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda,Maryland, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Carolina Center for Genome Sciences, Chapel Hill, North Carolina, USA. · Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan. · Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. · Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · School of Medicine, Chung Shan Medical University, Taichung, Taiwan. · Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. · National Taiwan University College of Medicine, Taipei, Taiwan. · Centre for Non-Communicable Disease, Karachi, Pakistan. · School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. · National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh. · National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. · Wellcome Trust Sanger Institute, Hinxton, UK. · British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK. ·Nat Genet · Pubmed #28530674.

ABSTRACT: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10

22 Article ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. 2017

Stitziel, Nathan O / Khera, Amit V / Wang, Xiao / Bierhals, Andrew J / Vourakis, A Christina / Sperry, Alexandra E / Natarajan, Pradeep / Klarin, Derek / Emdin, Connor A / Zekavat, Seyedeh M / Nomura, Akihiro / Erdmann, Jeanette / Schunkert, Heribert / Samani, Nilesh J / Kraus, William E / Shah, Svati H / Yu, Bing / Boerwinkle, Eric / Rader, Daniel J / Gupta, Namrata / Frossard, Philippe M / Rasheed, Asif / Danesh, John / Lander, Eric S / Gabriel, Stacey / Saleheen, Danish / Musunuru, Kiran / Kathiresan, Sekar / Anonymous261203. ·Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Electronic address: nstitziel@wustl.edu. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. · Harvard College, Harvard University, Cambridge, Massachusetts. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. · Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina. · Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom. · Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: kmus@mail.med.upenn.edu. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. Electronic address: skathiresan@partners.org. ·J Am Coll Cardiol · Pubmed #28385496.

ABSTRACT: BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

23 Article Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease. 2017

Khera, Amit V / Won, Hong-Hee / Peloso, Gina M / O'Dushlaine, Colm / Liu, Dajiang / Stitziel, Nathan O / Natarajan, Pradeep / Nomura, Akihiro / Emdin, Connor A / Gupta, Namrata / Borecki, Ingrid B / Asselta, Rosanna / Duga, Stefano / Merlini, Piera Angelica / Correa, Adolfo / Kessler, Thorsten / Wilson, James G / Bown, Matthew J / Hall, Alistair S / Braund, Peter S / Carey, David J / Murray, Michael F / Kirchner, H Lester / Leader, Joseph B / Lavage, Daniel R / Manus, J Neil / Hartzel, Dustin N / Samani, Nilesh J / Schunkert, Heribert / Marrugat, Jaume / Elosua, Roberto / McPherson, Ruth / Farrall, Martin / Watkins, Hugh / Lander, Eric S / Rader, Daniel J / Danesh, John / Ardissino, Diego / Gabriel, Stacey / Willer, Cristen / Abecasis, Gonçalo R / Saleheen, Danish / Dewey, Frederick E / Kathiresan, Sekar / Anonymous7860898. ·Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston. · Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts5Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. · Regeneron Genetics Center, Tarrytown, New Jersey. · Department of Public Health Sciences, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. · Department of Medicine, Washington University School of Medicine, St Louis, Missouri9Department of Genetics, Washington University School of Medicine, St Louis, Missouri10McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. · Department of Biomedical Sciences, Humanitas University, Milan, Italy12Humanitas Clinical and Research Center, Milan, Italy. · Ospedale Niguarda, Milano, Italy. · Department of Medicine, University of Mississippi Medical Center, Jackson. · Munich Heart Alliance, München, Germany16Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson. · NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. · Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds University, Leeds, United Kingdom. · Geisinger Health System, Danville, Pennsylvania. · Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany. · Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain. · University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom24Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Department of Genetics, University of Pennsylvania, Philadelphia. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom27Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom28NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom29Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy31Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor33Department of Human Genetics, University of Michigan, Ann Arbor34Department of Internal Medicine, University of Michigan, Ann Arbor. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. ·JAMA · Pubmed #28267856.

ABSTRACT: Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

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

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

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

25 Article Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. 2016

Natarajan, Pradeep / Bis, Joshua C / Bielak, Lawrence F / Cox, Amanda J / Dörr, Marcus / Feitosa, Mary F / Franceschini, Nora / Guo, Xiuqing / Hwang, Shih-Jen / Isaacs, Aaron / Jhun, Min A / Kavousi, Maryam / Li-Gao, Ruifang / Lyytikäinen, Leo-Pekka / Marioni, Riccardo E / Schminke, Ulf / Stitziel, Nathan O / Tada, Hayato / van Setten, Jessica / Smith, Albert V / Vojinovic, Dina / Yanek, Lisa R / Yao, Jie / Yerges-Armstrong, Laura M / Amin, Najaf / Baber, Usman / Borecki, Ingrid B / Carr, J Jeffrey / Chen, Yii-Der Ida / Cupples, L Adrienne / de Jong, Pim A / de Koning, Harry / de Vos, Bob D / Demirkan, Ayse / Fuster, Valentin / Franco, Oscar H / Goodarzi, Mark O / Harris, Tamara B / Heckbert, Susan R / Heiss, Gerardo / Hoffmann, Udo / Hofman, Albert / Išgum, Ivana / Jukema, J Wouter / Kähönen, Mika / Kardia, Sharon L R / Kral, Brian G / Launer, Lenore J / Massaro, Joe / Mehran, Roxana / Mitchell, Braxton D / Mosley, Thomas H / de Mutsert, Renée / Newman, Anne B / Nguyen, Khanh-Dung / North, Kari E / O'Connell, Jeffrey R / Oudkerk, Matthijs / Pankow, James S / Peloso, Gina M / Post, Wendy / Province, Michael A / Raffield, Laura M / Raitakari, Olli T / Reilly, Dermot F / Rivadeneira, Fernando / Rosendaal, Frits / Sartori, Samantha / Taylor, Kent D / Teumer, Alexander / Trompet, Stella / Turner, Stephen T / Uitterlinden, Andre G / Vaidya, Dhananjay / van der Lugt, Aad / Völker, Uwe / Wardlaw, Joanna M / Wassel, Christina L / Weiss, Stefan / Wojczynski, Mary K / Becker, Diane M / Becker, Lewis C / Boerwinkle, Eric / Bowden, Donald W / Deary, Ian J / Dehghan, Abbas / Felix, Stephan B / Gudnason, Vilmundur / Lehtimäki, Terho / Mathias, Rasika / Mook-Kanamori, Dennis O / Psaty, Bruce M / Rader, Daniel J / Rotter, Jerome I / Wilson, James G / van Duijn, Cornelia M / Völzke, Henry / Kathiresan, Sekar / Peyser, Patricia A / O'Donnell, Christopher J / Anonymous3111076. · ·Circ Cardiovasc Genet · Pubmed #27872105.

ABSTRACT: BACKGROUND: The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. METHODS AND RESULTS: We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10 CONCLUSIONS: Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

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