Abstract
Genomics, or the study of genomes, is concerned with understanding how the deoxyribonucleic acid (DNA) of which genomes are constituted contributes to making an organism unique. Accordingly, human genomics focuses on how DNA sequences produce individuals’ traits, e.g., skin color and cholesterol levels, and contribute to diseases, e.g., myocardial infarction and diabetes mellitus. The last decade has witnessed a remarkable leap forward in the use of genomics technology to understand human traits and diseases, to the point that new discoveries regarding what makes each person unique are being widely reported in the press and advertised by companies to the lay public. Although currently the clinical utility of genomics is limited, there are high expectations that it will become increasingly employed in practice in the near future. Discussions with patients of the implications of genomics – whether it is in the form of genetic testing for disease risk, pharmacogenomics, or personalized medicine – will be unavoidable for primary care providers. This chapter seeks to (1) explain the basic biology underlying genomics technology; (2) describe the current and potential future uses of genomics to improve patient care, particularly in cardiovascular medicine; and (3) set realistic expectations for the utility of genomics and explore the ethical implications of the technology.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Recommended Reading
O’Donnell CJ, Nabel EG. Genomics of cardiovascular disease. N Engl J Med. 2011;365:2098–109.
Ganesh SK, Arnett DK, Assimes TL, et al. Genetics and genomics for the prevention and treatment of cardiovascular disease: update: a scientific statement from the American Heart Association. Circulation. 2013;128:2813–51.
Musunuru K, Hickey KT, Al-Khatib SM, et al. Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American Heart Association. Circ Cardiovasc Genet. 2015;8:216–42.
References
Musunuru K, Kathiresan S. HapMap and mapping genes for cardiovascular disease. Circ Cardiovasc Genet. 2008;1:66–71.
Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science (New York, NY). 2007;316:1491–3.
McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science (New York, NY). 2007;316:1488–91.
Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443–53.
Deloukas P, Kanoni S, Willenborg C, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013;45:25–33.
Lu X, Wang L, Chen S, et al. Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nat Genet. 2012;44:890–4.
Nikpay M, Goel A, Won HH, et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;47:1121–30.
O'Donnell CJ, Kavousi M, Smith AV, et al. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation. 2011;124:2855–64.
Schunkert H, Konig IR, Kathiresan S, et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011;43:333–8.
Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–7.
Benjamin EJ, Rice KM, Arking DE, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81.
den Hoed M, Eijgelsheim M, Esko T, et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet. 2013;45:621–31.
Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet. 2012;44:670–5.
Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4.
Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–8.
Marcus GM, Alonso A, Peralta CA, et al. European ancestry as a risk factor for atrial fibrillation in African Americans. Circulation. 2010;122:2009–15.
Sandhu MS, Waterworth DM, Debenham SL, et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet (London, England). 2008;371:483–91.
Wallace C, Newhouse SJ, Braund P, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008;82:139–49.
Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–9.
Kathiresan S, Melander O, Guiducci C, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40:189–97.
Demirkan A, Amin N, Isaacs A, et al. Genetic architecture of circulating lipid levels. Eur J Hum Genet. 2011;19:813–9.
Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65.
Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13.
Waterworth DM, Ricketts SL, Song K, et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 2010;30:2264–76.
Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83.
Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, NY). 2007;316:1331–6.
Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science (New York, NY). 2007;316:1341–5.
Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science (New York, NY). 2007;316:1336–41.
Cho YS, Chen CH, Hu C, et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet. 2011;44:67–72.
Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105–16.
Hara K, Fujita H, Johnson TA, et al. Genome-wide association study identifies three novel loci for type 2 diabetes. Hum Mol Genet. 2014;23:239–46.
Kim YJ, Go MJ, Hu C, et al. Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat Genet. 2011;43:990–5.
Li H, Gan W, Lu L, et al. A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes. 2013;62:291–8.
Ng MC, Shriner D, Chen BH, et al. Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet. 2014;10:e1004517.
Saxena R, Hivert MF, Langenberg C, et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet. 2010;42:142–8.
Saxena R, Saleheen D, Been LF, et al. Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. Diabetes. 2013;62:1746–55.
Tabassum R, Chauhan G, Dwivedi OP, et al. Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21. Diabetes. 2013;62:977–86.
Unoki H, Takahashi A, Kawaguchi T, et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet. 2008;40:1098–102.
Voight BF, Scott LJ, Steinthorsdottir V, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42:579–89.
Williams AL, Jacobs SB, Moreno-Macias H, et al. Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature. 2014;506:97–101.
Yasuda K, Miyake K, Horikawa Y, et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet. 2008;40:1092–7.
Arking DE, Pfeufer A, Post W, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006;38:644–51.
Avery CL, Sethupathy P, Buyske S, et al. Fine-mapping and initial characterization of QT interval loci in African Americans. PLoS Genet. 2012;8:e1002870.
Newton-Cheh C, Eijgelsheim M, Rice KM, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet. 2009;41:399–406.
Pfeufer A, Sanna S, Arking DE, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41:407–14.
Smith JG, Avery CL, Evans DS, et al. Impact of ancestry and common genetic variants on QT interval in African Americans. Circ Cardiovasc Genet. 2012;5:647–55.
Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40:217–24.
Bown MJ, Jones GT, Harrison SC, et al. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. Am J Hum Genet. 2011;89:619–27.
Bradley DT, Hughes AE, Badger SA, et al. A variant in LDLR is associated with abdominal aortic aneurysm. Circ Cardiovasc Genet. 2013;6:498–504.
Gretarsdottir S, Baas AF, Thorleifsson G, et al. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat Genet. 2010;42:692–7.
Jones GT, Bown MJ, Gretarsdottir S, et al. A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Hum Mol Genet. 2013;22:2941–7.
van't Hof FN, Ruigrok YM, Lee CH, et al. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms. J Am Heart Assoc. 2016;5 https://doi.org/10.1161/JAHA.115.002603.
Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008;359:789–99.
Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012;5:257–64.
Mangravite LM, Engelhardt BE, Medina MW, et al. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature. 2013;502:377–80.
Postmus I, Trompet S, Deshmukh HA, et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun. 2014;5:5068.
Wahl S, Drong A, Lehne B, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2016;
Gusev A, Ko A, Shi H, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48:245–52.
Wilson KD, Shen P, Fung E, et al. A rapid, high-quality, cost-effective, comprehensive and expandable targeted next-generation sequencing assay for inherited heart diseases. Circ Res. 2015;117:603–11.
van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, et al. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy. Eur Heart J. 2014;35:2165–73.
Sadananda SN, Foo JN, Toh MT, et al. Targeted next-generation sequencing to diagnose disorders of HDL cholesterol. J Lipid Res. 2015;56:1993–2001.
Patel AP, Peloso GM, Pirruccello JP, et al. Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution. Atherosclerosis. 2016;250:63–8.
Lin H, Sinner MF, Brody JA, et al. Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. Heart Rhythm. 2014;11:452–7.
Futema M, Plagnol V, Whittall RA, Neil HA, Humphries SE. Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia. J Med Genet. 2012;49:644–9.
Fokstuen S, Makrythanasis P, Nikolaev S, et al. Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders. Clin Genet. 2014;85:365–70.
Fine PE, Gruer PJ, Maine N, Ponnighaus JM, Rees RJ, Stanford JL. Failure of Mycobacterium leprae soluble antigens to suppress delayed-type hypersensitivity reaction to tuberculin. Clin Exp Immunol. 1989;77:226–9.
Akinrinade O, Ollila L, Vattulainen S, et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015;36:2327–37.
Walsh R, Cook SA. Issues and challenges in diagnostic sequencing for inherited cardiac conditions. Clin Chem. 2016;63(1):116–28.
Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220–7.
Proust C, Empana JP, Boutouyrie P, et al. Contribution of rare and common genetic variants to plasma lipid levels and carotid stiffness and geometry: a Substudy of the Paris Prospective Study 3. Circ Cardiovasc Genet. 2015;8:628–36.
Golbus JR, Stitziel NO, Zhao W, et al. Common and rare genetic variation in CCR2, CCR5, or CX3CR1 and risk of atherosclerotic coronary heart disease and glucometabolic traits. Circ Cardiovasc Genet. 2016;9:250–8.
Glessner JT, Bick AG, Ito K, et al. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ Res. 2014;115:884–96.
Peloso GM, Auer PL, Bis JC, et al. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014;94:223–32.
Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46:352–6.
Holmen OL, Zhang H, Fan Y, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014;46:345–51.
Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.
Cunningham D, Danley DE, Geoghegan KF, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol. 2007;14:413–9.
Pandit S, Wisniewski D, Santoro JC, et al. Functional analysis of sites within PCSK9 responsible for hypercholesterolemia. J Lipid Res. 2008;49:1333–43.
Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol. 2005;25:2654–60.
Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101:7100–5.
Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 2004;279:50630–8.
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.
Kathiresan S, Myocardial Infarction Genetics C. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med. 2008;358:2299–300.
McPherson R, Kavaslar N. Statins for primary prevention of coronary artery disease. Lancet (London, England). 2007;369:1078; author reply 1079.
Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–900.
Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–18.
Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.
Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2015;36:560–5.
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2015;385:341–50.
Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2015;385:331–40.
Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–8.
Sabatine MS, Wasserman SM, Stein EA. PCSK9 inhibitors and cardiovascular events. N Engl J Med. 2015;373:774–5.
Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.
Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 inhibitors – the clinical benefit of lipid drugs. N Engl J Med. 2015;373:1588–91.
Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015;518:102–6.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.
Emdin CA, Khera AV, Natarajan P, et al. Phenotypic characterization of genetically lowered human lipoprotein(a) levels. J Am Coll Cardiol. 2016;68:2761–72.
Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet (London, England). 2014;384:618–25.
Rader DJ. New therapeutic approaches to the treatment of dyslipidemia. Cell Metab. 2016;23:405–12.
Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.
Kingwell BA, Chapman MJ, Kontush A, Miller NE. HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov. 2014;13:445–64.
Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.
Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99.
Connelly MA, Parry TJ, Giardino EC, et al. Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition. J Cardiovasc Pharmacol. 2010;55:459–68.
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22.
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet (London, England). 2012;380:572–80.
Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015;36:539–50.
Haase CL, Tybjaerg-Hansen A, Qayyum AA, Schou J, Nordestgaard BG, Frikke-Schmidt R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012;97:E248–56.
Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science (New York, NY). 2016;351:1166–71.
Saleheen D, Scott R, Javad S, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3:507–13.
Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371:2383–93.
Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35.
Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–52.
Stitziel NO, Stirrups KE, Masca NG, et al. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med. 2016;374:1134–44.
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science (New York, NY). 2008;322:1702–5.
Khetarpal SA, Qamar A, Millar JS, Rader DJ. Targeting ApoC-III to reduce coronary disease risk. Curr Atheroscler Rep. 2016;18:54.
Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.
Dewey FE, Gusarova V, O'Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;374:1123–33.
Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31.
Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–6.
Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–47.
Desai U, Lee EC, Chung K, 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 U S A. 2007;104:11766–71.
Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res. 2015;56:1296–307.
Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308–17.
Kathiresan S, Melander O, Anevski D, et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med. 2008;358:1240–9.
Musunuru K, Kral BG, Blumenthal RS, et al. The use of high-sensitivity assays for C-reactive protein in clinical practice. Nat Clin Pract Cardiovasc Med. 2008;5:621–35.
Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116:2563–70.
Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;83:460–70.
Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet (London, England). 2009;373:309–17.
Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–62.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–75.
Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363:1704–14.
Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet (London, England). 2010;376:1320–8.
Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304:1821–30.
Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306:2704–14.
Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ (Clinical research ed). 2011;343:d4588.
Doll JA, Neely ML, Roe MT, et al. Impact of CYP2C19 metabolizer status on patients with ACS treated with Prasugrel versus Clopidogrel. J Am Coll Cardiol. 2016;67:936–47.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Khetarpal, S.A., Musunuru, K. (2019). Deciphering Cardiovascular Genomics and How They Apply to Cardiovascular Disease Prevention. In: Toth, P., Cannon, C. (eds) Comprehensive Cardiovascular Medicine in the Primary Care Setting. Contemporary Cardiology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-97622-8_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-97622-8_6
Published:
Publisher Name: Humana Press, Cham
Print ISBN: 978-3-319-97621-1
Online ISBN: 978-3-319-97622-8
eBook Packages: MedicineMedicine (R0)