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Coronary Artery Disease: HELP
Articles by Daniel J. Rader
Based on 73 articles published since 2010
(Why 73 articles?)
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Between 2010 and 2020, Dan Rader wrote the following 73 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Polygenic Risk Scores and Coronary Artery Disease: Ready for Prime Time? 2020

Levin, Michael G / Rader, Daniel J. ·Division of Cardiovascular Medicine (M.G.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia. · Department of Medicine (M.G.L., D.J.R.), University of Pennsylvania Perelman School of Medicine, Philadelphia. · Department of Genetics (D.J.R.), University of Pennsylvania Perelman School of Medicine, Philadelphia. ·Circulation · Pubmed #32091922.

ABSTRACT: -- No abstract --

2 Editorial Apolipoprotein A-I Infusion Therapies for Coronary Disease: Two Outs in the Ninth Inning and Swinging for the Fences. 2018

Rader, Daniel J. ·Department of Genetics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at University of Pennsylvania, Philadelphia. ·JAMA Cardiol · Pubmed #30046821.

ABSTRACT: -- No abstract --

3 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 --

4 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.

5 Editorial Apolipoprotein A-I and cholesterol efflux: the good, the bad, and the modified. 2014

Javaheri, Ali / Rader, Daniel J. ·From the Department of Medicine and Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. · From the Department of Medicine and Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. rader@mail.med.upenn.edu. ·Circ Res · Pubmed #24855198.

ABSTRACT: -- No abstract --

6 Review Angiopoietin-like protein 4: A therapeutic target for triglycerides and coronary disease? 2018

Olshan, David S / Rader, Daniel J. ·Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: david.olshan@uphs.upenn.edu. · Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. ·J Clin Lipidol · Pubmed #29548670.

ABSTRACT: The angiopoietin-like proteins are a family of proteins that share structural similarities to the angiopoietins. These proteins have been described to play a key role in the regulation of a myriad of physiologic processes, including serving as essential modulators of lipid and glucose metabolism. Angiopoietin-like protein 4 (ANGPTL4) is a key regulator of lipoprotein lipase, and its modulation has been shown to significantly impact the body's processing and distribution of triglycerides and cholesterol. Although more research remains to elucidate the full range of mechanisms through which ANGPTL4 affects triglyceride and cholesterol homeostasis, current research has associated decreased ANGPTL4 function with a beneficial effect on lipid parameters and overall cardiovascular disease risk, opening the possibility of ANGPTL4 as a new therapeutic target for the treatment of cardiovascular disease.

7 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.

8 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.

9 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.

10 Review Human genetics of atherothrombotic disease and its risk factors. 2015

Rader, Daniel J. ·From the Departments of Genetics and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. rader@mail.med.upenn.edu. ·Arterioscler Thromb Vasc Biol · Pubmed #25810293.

ABSTRACT: -- No abstract --

11 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.

12 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.

13 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.

14 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.

15 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.

16 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.

17 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.

18 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 .).

19 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.

20 Article Association of serum androgens and coronary artery calcium scores in women. 2019

Penn, Courtney A / Chan, Jessica / Mesaros, Clementina / Snyder, Nathaniel W / Rader, Daniel J / Sammel, Mary D / Dokras, Anuja. ·Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania. · Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: adokras@obgyn.upenn.edu. ·Fertil Steril · Pubmed #31200968.

ABSTRACT: OBJECTIVE: To determine the association between serum androgens measured by high-resolution liquid chromatography-mass spectrometry and coronary artery calcium (CAC) scores. DESIGN: Cross-sectional study. SETTING: Academic institution. PATIENT(S): A total of 239 women, aged 40-75 years, with CAC testing and complete cardiovascular disease risk evaluation. Total T, DHEA, and androstenedione were measured using high-resolution liquid chromatography-mass spectrometry, whereas E INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Independent associations between CAC scores and sex steroids. RESULT(S): Overall, 164 subjects had a CAC score < 10, 48 had a CAC score between 10 and 100, and 27 had a score > 100. There were no differences in sex hormone levels between women with CAC scores > 10 vs. CAC scores ≤ 10. In multivariable models adjusting for age, body mass index, and low-density lipoprotein cholesterol, a higher T/E CONCLUSION(S): In the general population, there are mixed reports regarding the relationship between serum androgens and risk factors for cardiovascular disease, and limited information on the relationship between androgens and subclinical atherosclerosis. Our study shows that increased androgens relative to estrogens may have a weak but independent association with subclinical atherosclerosis, as measured by CAC scores.

21 Article Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. 2018

Sun, Yan V / Damrauer, Scott M / Hui, Qin / Assimes, Themistocles L / Ho, Yuk-Lam / Natarajan, Pradeep / Klarin, Derek / Huang, Jie / Lynch, Julie / DuVall, Scott L / Pyarajan, Saiju / Honerlaw, Jacqueline P / Gaziano, J Michael / Cho, Kelly / Rader, Daniel J / O'Donnell, Christopher J / Tsao, Philip S / Wilson, Peter W F. ·Department of Epidemiology, Emory University Rollins School of Public Health. · Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA. · Corporal Michael Crescenz VA Medical Center,University of Pennsylvania, Philadelphia, PA. · VA Palo Alto Health Care System, Department of Medicine, Stanford University School of Medicine, Stanford, CA. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston. · Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Program in Medical & Population Genetics, Broad Institute of Harvard & MIT, Cambridge. · Massachusetts General Hospital, Boston, MA, Broad Institute of Harvard & MIT, Cambridge. · University of Massachusetts College of Nursing & Health Sciences, Boston, MA. · Department of Veterans Affairs Salt Lake City Health Care System. · University of Utah, School of Medicine, Salt Lake City, UT. · Department of Medicine, Brigham and Women's Hospital, Boston, MA. · Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA. · Harvard Medical School, Boston, MA. · Atlanta VA Medical Center and Emory Clinical Cardiovascular Research Institute, Atlanta, GA. ·Circ Genom Precis Med · Pubmed #31106297.

ABSTRACT: Background: Familial hypercholesterolemia (FH) is characterized by inherited high levels of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Over a thousand low-frequency variants in Methods: We examined the individual and collective association between putatively pathogenic FH variants included on the MVP biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters. Results: We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4-80.2 mg/dL). Phenotypic effects were similar for European and African Americans despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL, p=1.2×10 Conclusions: The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multi-ethnic populations is needed to accurately infer at-risk individuals from genetic screening.

22 Article Genomic Risk Stratification Predicts All-Cause Mortality After Cardiac Catheterization. 2018

Levin, Michael G / Kember, Rachel L / Judy, Renae / Birtwell, David / Williams, Heather / Arany, Zolt / Giri, Jay / Guerraty, Marie / Cappola, Tom / Anonymous3471116 / Chen, Jinbo / Rader, Daniel J / Damrauer, Scott M. ·Department of Medicine (M.G.L., D.B., H.W., Z.A, J.G., M.G., T.C., ), Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Department of Genetics (R.L.K., D.J.R.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Department of Surgery (R.J., S.M.D.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA (J.G., S.M.D.). · Department of Biostatistics, Epidemiology, and Informatics (J.C.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. ·Circ Genom Precis Med · Pubmed #30571185.

ABSTRACT: BACKGROUND: Coronary artery disease (CAD) is influenced by genetic variation and traditional risk factors. Polygenic risk scores (PRS), which can be ascertained before the development of traditional risk factors, have been shown to identify individuals at elevated risk of CAD. Here, we demonstrate that a genome-wide PRS for CAD predicts all-cause mortality after accounting for not only traditional cardiovascular risk factors but also angiographic CAD itself. METHODS: Individuals who underwent coronary angiography and were enrolled in an institutional biobank were included; those with prior myocardial infarction or heart transplant were excluded. Using a pruning-and-thresholding approach, a genome-wide PRS comprised of 139 239 variants was calculated for 1503 participants who underwent coronary angiography and genotyping. Individuals were categorized into high PRS (hiPRS) and low-PRS control groups using the maximally selected rank statistic. Stratified analysis based on angiographic findings was also performed. The primary outcome was all-cause mortality following the index coronary angiogram. RESULTS: Individuals with hiPRS were younger than controls (66 years versus 69 years; P=2.1×10 CONCLUSIONS: A genome-wide PRS improves risk stratification when added to traditional risk factors and coronary angiography. Individuals without angiographic CAD but with hiPRS remain at significantly elevated risk of mortality.

23 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.

24 Article Mining the Stiffness-Sensitive Transcriptome in Human Vascular Smooth Muscle Cells Identifies Long Noncoding RNA Stiffness Regulators. 2018

Yu, Christopher K / Xu, Tina / Assoian, Richard K / Rader, Daniel J. ·From the Perelman School of Medicine (C.K.Y.), Department of Systems Pharmacology and Translational Therapeutics (T.X., R.K.A.), Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics (T.X., R.K.A.), and Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine (D.J.R.), University of Pennsylvania, Philadelphia. · This manuscript was sent to Zahi Fayad, Consulting Editor, for review by expert referees, editorial decision, and final disposition. · From the Perelman School of Medicine (C.K.Y.), Department of Systems Pharmacology and Translational Therapeutics (T.X., R.K.A.), Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics (T.X., R.K.A.), and Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine (D.J.R.), University of Pennsylvania, Philadelphia. rader@pennmedicine.upenn.edu. · This manuscript was sent to Zahi Fayad, Consulting Editor, for review by expert referees, editorial decision, and final disposition. rader@pennmedicine.upenn.edu. ·Arterioscler Thromb Vasc Biol · Pubmed #29051139.

ABSTRACT: OBJECTIVE: Vascular extracellular matrix stiffening is a risk factor for aortic and coronary artery disease. How matrix stiffening regulates the transcriptome profile of human aortic and coronary vascular smooth muscle cells (VSMCs) is not well understood. Furthermore, the role of long noncoding RNAs (lncRNAs) in the cellular response to stiffening has never been explored. This study characterizes the stiffness-sensitive (SS) transcriptome of human aortic and coronary VSMCs and identifies potential key lncRNA regulators of stiffness-dependent VSMC functions. APPROACH AND RESULTS: Aortic and coronary VSMCs were cultured on hydrogel substrates mimicking physiological and pathological extracellular matrix stiffness. Total RNAseq was performed to compare the SS transcriptome profiles of aortic and coronary VSMCs. We identified 3098 genes (2842 protein coding and 157 lncRNA) that were stiffness sensitive in both aortic and coronary VSMCs (false discovery rate <1%). Hierarchical clustering revealed that aortic and coronary VSMCs grouped by stiffness rather than cell origin. Conservation analyses also revealed that SS genes were more conserved than stiffness-insensitive genes. These VSMC SS genes were less tissue-type specific and expressed in more tissues than stiffness-insensitive genes. Using unbiased systems analyses, we identified MALAT1 as an SS lncRNA that regulates stiffness-dependent VSMC proliferation and migration in vitro and in vivo. CONCLUSIONS: This study provides the transcriptomic landscape of human aortic and coronary VSMCs in response to extracellular matrix stiffness and identifies novel SS human lncRNAs. Our data suggest that the SS transcriptome is evolutionarily important to VSMCs function and that SS lncRNAs can act as regulators of stiffness-dependent phenotypes.

25 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 / Anonymous11401124 / Anonymous11411124 / Anonymous11421124 / Anonymous11431124 / Anonymous11441124 / 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.

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