Genetics of coronary artery disease: discovery, biology and clinical translation (original) (raw)

• Ford, E. S. et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N. Engl. J. Med. 356, 2388–2398 (2007).
  Article CAS PubMed Google Scholar
• Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).
  Article PubMed Google Scholar
• Mozaffarian, D. et al. Heart disease and stroke statistics — 2016 update: a report from the American Heart Association. Circulation 133, e38–e360 (2016).
  PubMed Google Scholar
• Khera, A. V. et al. Genetic risk, adherence to a healthy lifestyle, and risk of coronary disease. N. Engl. J. Med. 375, 2349–2358 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Gertler, M. M., Garn, S. M. & White, P. D. Young candidates for coronary heart disease. JAMA 147, 621–625 (1951).
  Article CAS Google Scholar
• Marenberg, M. E., Risch, N., Berkman, L. F., Floderus, B. & de Faire, U. Genetic susceptibility to death from coronary heart disease in a study of twins. N. Engl. J. Med. 330, 1041–1046 (1994). The first large-scale prospective study of twins to confirm an increased risk of early-onset CAD among highly related individuals.
  Article CAS PubMed Google Scholar
• Zdravkovic, S. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J. Intern. Med. 252, 247–254 (2002).
  Article CAS PubMed Google Scholar
• Won, H. H. et al. Disproportionate contributions of select genomic compartments and cell types to genetic risk for coronary artery disease. PLoS Genet. 11, e1005622 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Lloyd-Jones, D. M. et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 291, 2204–2211 (2004).
  Article CAS PubMed Google Scholar
• Murabito, J. M. et al. Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA 294, 3117–3123 (2005).
  Article CAS PubMed Google Scholar
• Watkins, H. & Farrall, M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat. Rev. Genet. 7, 163–173 (2006).
  Article CAS PubMed Google Scholar
• Müller, C. Xanthomata, hypercholesterolemia, angina pectoris. J. Intern. Med. 89, 75–84 (1938).
  Google Scholar
• Lehrman, M. A. et al. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227, 140–146 (1985). The first family-based study to identify a discrete mutation in a single gene predisposing to CAD (familial hypercholesterolaemia).
  Article CAS PubMed PubMed Central Google Scholar
• Soria, L. F. et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc. Natl Acad. Sci. USA 86, 587–591 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).
  Article CAS PubMed Google Scholar
• Garcia, C. K. et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292, 1394–1398 (2001).
  Article CAS PubMed Google Scholar
• Berge, K. E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).
  Article CAS PubMed Google Scholar
• Wang, L., Fan, C., Topol, S. E., Topol, E. J. & Wang, Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302, 1578–1581 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Lieb, W. et al. Lack of association between the MEF2A gene and myocardial infarction. Circulation 117, 185–191 (2008).
  Article CAS PubMed Google Scholar
• Mani, A. et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315, 1278–1282 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Keramati, A. R. et al. A form of the metabolic syndrome associated with mutations in DYRK1B. N. Engl. J. Med. 370, 1909–1919 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014). Provides a framework for systematically assessing a potentially causal relationship between a given genetic variant and risk of human disease.
  Article CAS PubMed PubMed Central Google Scholar
• Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zuk, O. et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl Acad. Sci. USA 111, E455–E464 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Samani, N. J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).
  Article CAS PubMed Google Scholar
• McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ye, S., Willeit, J., Kronenberg, F., Xu, Q. & Kiechl, S. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J. Am. Coll. Cardiol. 52, 378–384 (2008).
  Article CAS PubMed Google Scholar
• Helgadottir, A. et al. The same sequence variant on9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40, 217–224 (2008).
  Article CAS PubMed Google Scholar
• Smith, J. G. et al. Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: a large-scale genetic association study. Circ. Cardiovasc. Genet. 2, 159–164 (2009).
  Article CAS PubMed Google Scholar
• Jarinova, O. et al. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler. Thromb. Vasc. Biol. 29, 1671–1677 (2009).
  Article CAS PubMed Google Scholar
• Holdt, L. M. et al. ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler. Thromb. Vasc. Biol. 30, 620–627 (2010).
  Article CAS PubMed Google Scholar
• Harismendy, O. et al. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature 470, 264–268 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2010).
• Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Coronary Artery Disease Genetics (C4D) Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat. Genet. 43, 339–344 (2011).
• IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 7, e1002260 (2011).
• CARDIoGRAMplusC4D Consortium et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).
• Nikpay, M. et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47, 1121–1130 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• So, H. C., Gui, A. H., Cherny, S. S. & Sham, P. C. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet. Epidemiol. 35, 310–317 (2011).
  Article PubMed Google Scholar
• Flannick, J. & Florez, J. C. Type 2 diabetes: genetic data sharing to advance complex disease research. Nat. Rev. Genet. 17, 535–559 (2016).
  Article CAS PubMed Google Scholar
• Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511, 421–427 (2014).
• Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N. Engl. J. Med. 374, 1134–1144 (2016).
• Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ehret, G. B. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat. Genet. 48, 1171–1184 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Erdmann, J. et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504, 432–436 (2013).
  Article CAS PubMed Google Scholar
• Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Do, R. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015). The first large study to use whole-exome sequencing to examine the relationship of rare variants in each gene with CAD.
  Article CAS PubMed Google Scholar
• Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).
  Article CAS PubMed Google Scholar
• Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006). Links inactivating mutations in PCSK9 with significantly reduced LDL cholesterol and risk of incident CAD.
  Article CAS PubMed Google Scholar
• Nioi, P. et al. Variant ASGR1 associated with a reduced risk of coronary artery disease. N. Engl. J. Med. 374, 2131–2141 (2016).
  Article CAS PubMed Google Scholar
• Khera, A. V. et al. Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. JAMA http://dx.doi.org/10.1001/jama.2017.0972 (2017).
• Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjærg-Hansen, A. Loss-of- function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).
  Article CAS PubMed Google Scholar
• Crosby, J. et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).
  Article CAS PubMed Google Scholar
• Dewey, F. E. et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N. Engl. J. Med. 374, 1123–1133 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010). The first paper to characterize the mechanism linking a non-coding variant with changes in gene regulation related to LDL cholesterol metabolism.
  Article CAS PubMed PubMed Central Google Scholar
• Strong, A. et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J. Clin. Invest. 122, 2807–2816 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Reilly, M. P. et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377, 383–392 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Pu, X. et al. ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. Am. J. Hum. Genet. 92, 366–374 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Bauer, R. C. et al. Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131, 1202–1213 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Kessler, T. et al. ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1. Circulation 131, 1191–1201 (2015).
  Article CAS PubMed Google Scholar
• DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 (2016).
  Article PubMed Google Scholar
• Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 203–214 (2010).
  Article CAS PubMed Google Scholar
• Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013). This Review article describes the potential utility of human genetics to expedite drug development.
  Article CAS PubMed Google Scholar
• Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).
• Voight, B. F. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).
  Article CAS PubMed Google Scholar
• Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Myocardial Infarction Genetics Consortium Investigators. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072–2082 (2014).
• Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).
  Article CAS PubMed Google Scholar
• Lp-PLA(2) Studies Collaboration et al. Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 375, 1536–1544 (2010).
• Wilensky, R. L. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat. Med. 14, 1059–1066 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• The STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370, 1702–1711 (2014).
• O'Donoghue, M. L. et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 312, 1006–1015 (2014).
  Article CAS PubMed Google Scholar
• Polfus, L. M. et al. Coronary heart disease and genetic variants with low phospholipase A2 activity. N. Engl. J. Med. 372, 295–296 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Casas, J. P. et al. PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry. Circulation 121, 2284–2293 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).
  Article CAS PubMed Google Scholar
• Sabatine, M. S. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).
  Article CAS PubMed Google Scholar
• Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015).
  Article CAS PubMed Google Scholar
• Tsimikas, S. et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386, 1472–1483 (2015).
  Article CAS PubMed Google Scholar
• Swerdlow, D. I. et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385, 351–361 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Sattar, N. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735–742 (2010).
  Article CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01252953 (2016).
• Neale, B. M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl Acad. Sci. USA 107, 7395–7400 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl Acad. Sci. USA 107, 7401–7406 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, C. Y. et al. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nat. Commun. 6, 6063 (2015).
  Article CAS PubMed Google Scholar
• Bush, W. S., Oetjens, M. T. & Crawford, D. C. Unravelling the human genome–phenome relationship using phenome-wide association studies. Nat. Rev. Genet. 17, 129–145 (2016).
  Article CAS PubMed Google Scholar
• Emdin, C. A. et al. Phenotypic characterization of genetically lowered human lipoprotein(a) levels. J. Am. Coll. Cardiol. 68, 2761–2772 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Sawabe, M. et al. Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort study (the JMS cohort study). PLoS ONE. 7, e31954 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mora, S. et al. Lipoprotein(a) and risk of type 2 diabetes. Clin. Chem. 56, 1252–1260 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lichtenstein, L. et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab. 12, 580–592 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Desai, U. et al. Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc. Natl Acad. Sci. USA 104, 11766–11771 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• McClellan, J. & King, M. C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
  Article CAS PubMed Google Scholar
• Nelson, M. R. et al. The genetics of drug efficacy: opportunities and challenges. Nat. Rev. Genet. 17, 197–206 (2016).
  Article CAS PubMed Google Scholar
• Paynter, N. P., Ridker, P. M. & Chasman, D. I. Are genetic tests for atherosclerosis ready for routine clinical use? Circ. Res. 118, 607–619 (2016).
  Article CAS PubMed Google Scholar
• Umans-Eckenhausen, M. A., Defesche, J. C., Sijbrands, E. J., Scheerder, R. L. & Kastelein, J. J. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357, 165–168 (2001).
  Article CAS PubMed Google Scholar
• Nordestgaard, B. G. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J. 34, 3478–3490 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Khera, A. V. et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J. Am. Coll. Cardiol. 67, 2578–2589 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Talmud, P. J. et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case–control study. Lancet 381, 1293–1301 (2013).
  Article CAS PubMed Google Scholar
• Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1138 (1994).
• Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380, 581–590 (2012).
• Chatterjee, N., Shi, J. & García-Closas, M. Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat. Rev. Genet. 17, 392–406 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Kathiresan, S. et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N. Engl. J. Med. 358, 1240–1249 (2008).
  Article CAS PubMed Google Scholar
• Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 1393–1400 (2010).
  Article PubMed PubMed Central Google Scholar
• Tada, H. et al. Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history. Eur. Heart J. 37, 561–567 (2016).
  Article CAS PubMed Google Scholar
• Abraham, G. et al. Genomic prediction of coronary heart disease. Eur Heart J. 37, 3267–3278 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Mega, J. L. et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 385, 2264–2271 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Kullo, I. J. et al. Incorporating a genetic risk score into coronary heart disease risk estimates: effect on low-density lipoprotein cholesterol levels (the MI-GENES clinical trial). Circulation 133, 1181–1188 (2016).
  Article PubMed PubMed Central Google Scholar
• Wellcome Trust Case Control Consortium et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).
• ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).
• GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
• Stylianou, I. M., Bauer, R. C., Reilly, M. P. & Rader, D. J. Genetic basis of atherosclerosis: insights from mice and humans. Circ. Res. 110, 337–355 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Nurnberg, S. T. et al. From loci to biology: functional genomics of genome-wide association for coronary disease. Circ. Res. 118, 586–606 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Narasimhan, V. M. et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science 352, 474–477 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Saleheen, D. et al. Human knockouts in a cohort with a high rate of consanguinity. Preprint at bioRxiv http://dx.doi.org/10.1101/031518 (2015). Identifies humans with inactivating mutations ('knockouts') in ∼1,000 genes and genotype-based call back to understand relevant physiology.
  Google Scholar
• Choudhry, N. K. et al. Full coverage for preventive medications after myocardial infarction. N. Engl. J. Med. 365, 2088–2097 (2011).
  Article CAS PubMed Google Scholar
• Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014). Proof-of-concept study in a mouse model that permanent disruption of PCSK9 using gene editing can decrease LDL cholesterol and atherosclerosis.
  Article CAS PubMed PubMed Central Google Scholar
• Lander, E. S. Brave new genome. N. Engl. J. Med. 373, 5–8 (2015).
  Article CAS PubMed Google Scholar
• Blendon, R. J., Gorski, M. T. & Benson, J. M. The public and the gene-editing revolution. N. Engl. J. Med. 374, 1406–1411 (2016).
  Article PubMed Google Scholar
• Libby, P. in Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine 10th edn (eds Bonow, R. O., Mann, D. L., Zipes, D. P. & Libby, P.) 873–890 (Saunders, 2014).
  Google Scholar
• Ridker, P. M., Libby, P. & Buring, J. E. in Braunwald's Heart Disease: a Textbook of Cardiovascular Medicine 10th edn (eds Bonow, R. O., Mann, D. L., Zipes, D. P. & Libby, P.) 891–933 (Saunders, 2014).
  Google Scholar
• Kessler, T., Vilne, B. & Schunkert, H. The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease. EMBO Mol. Med. 8, 688–701 (2016).
  Article CAS PubMed PubMed Central Google Scholar