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Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study

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Abstract

Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.

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References

  • Almontashiri NA, Fan M, Cheng BL, Chen HH, Roberts R, Stewart AF (2013) Interferon-γ activates expression of p15 and p16 regardless of 9p21.3 coronary artery disease risk genotype. J Am Coll Cardiol 61:143–147

    CAS  PubMed  Google Scholar 

  • American Diabetes Association (2004) Diagnosis and classification of diabetes mellitus. Diabetes Care 27:S5–S10

    Article  Google Scholar 

  • Assimes TL, Knowles JW, Basu A, Iribarren C, Southwick A, Tang H, Absher DLJ, Fair JM, Rubin GD et al (2008) Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet 17:2320–2328

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  CAS  PubMed  Google Scholar 

  • Brautbar A, Ballantyne CM, Lawson K, Nambi V, Chambless L, Folsom AR, Willerson JT, Boerwinkle E (2009) Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the Atherosclerosis Risk in Communities Study. Circ Cardiovasc Genet 2:279–285

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • CARDIoGRAMplusC4D Consortium, Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, Thompson JR, Ingelsson E, Saleheen D, Erdmann J, Goldstein BA et al (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45:25–33

    Article  CAS  PubMed  Google Scholar 

  • Chobanian AV (1992) Pathophysiology of hypertension. Am J Cardiol 70:3G–7G

    Article  CAS  PubMed  Google Scholar 

  • Cowper-Sal Iari R, Cole MD, Karagas MR, Lupien M, Moore JH (2011) Layers of epistasis: genome-wide regulatory networks and network approaches to genome-wide association studies. Wiley Interdiscip Rev Syst Biol Med 3:513–526

    Article  Google Scholar 

  • Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B (2010) Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet 6:e1000899

    Article  PubMed Central  PubMed  Google Scholar 

  • Do R, Xie C, Zhang X, Männistö S, Harald K, Islam S, Bailey SD, Rangarajan S, McQueen MJ, Diaz R (2012) The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study. PLoS Med 8:e1001106

    Google Scholar 

  • Dominguez-Brauer C, Brauer PM, Chen Y-J, Pimkina J, Raychaudhuri P (2010) Tumor suppression by ARF: gatekeeper and caretaker. Cell Cycle 9:86–89

    Article  CAS  PubMed  Google Scholar 

  • Dong L, Wang H, Wang DW, Ding H (2013) Association of chromosome 9p21 genetic variants with risk of coronary heart disease in the East Asian population: a meta-analysis. Ann Hum Genet 77:183–190

    Article  CAS  PubMed  Google Scholar 

  • Dyson G, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A, Sing CF (2007) An application of the patient rule-induction method for evaluating the contribution of the apolipoprotein E and lipoprotein lipase genes to predicting ischemic heart disease. Genet Epidemiol 31:515–527

    Article  PubMed Central  PubMed  Google Scholar 

  • Dyson G, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A, Sing CF (2009) Modifications to the patient rule-induction method that utilize non-additive combinations of genetic and environmental effects to define partitions that predict ischemic heart disease. Genet Epidemiol 33:317–324

    Article  PubMed Central  PubMed  Google Scholar 

  • Expert Panel of the National Cholesterol Education Program (2002) Detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). National Institutes of Health

  • Folsom AR, Nambi V, Pankow JS, Tang W, Farbakhsh K, Yamagishi K, Boerwinkle E (2012) Effect of 9p21 genetic variation on coronary heart disease is not modified by other risk markers. The Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 224:435–439

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frankel WN, Schork NJ (1996) Who’s afraid of epistasis? Nat Genet 14:371–373

    Article  CAS  PubMed  Google Scholar 

  • Freis ED (1969) Hypertension and atherosclerosis. Am J Med 46:735–740

    Article  CAS  PubMed  Google Scholar 

  • Friedman JH, Fisher NI (1999) Bump-hunting for high dimensional data. Stat Comp 9:123–143

    Article  Google Scholar 

  • Frikke-Schmidt R, Sing CF, Nordestgaard BG, Tybjaerg-Hansen A (2004) Gender- and age-specific contributions of additional DNA sequence variation in the 5′ regulatory region of the APOE gene to prediction of measures of lipid metabolism. Hum Genet 115:331–345

    Article  CAS  PubMed  Google Scholar 

  • Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnor P, Grande P, Tybjaerg-Hansen A (2008) Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299:2524–2532

    Article  CAS  PubMed  Google Scholar 

  • Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR (1977) High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 62:707–714

    Article  CAS  PubMed  Google Scholar 

  • Haase CL, Tybjaerg-Hansen A, Grande P, Frikke-Schmidt R (2010) Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab 95:E500–E510

    Article  CAS  PubMed  Google Scholar 

  • Harismendy O, Notani D, Song X, Rahim NG, Tanasa B, Heintzman N, Ren B, Fu XD, Topol EJ, Rosenfeld MG, Frazer KA (2011) 9p21 DNA variants associated with coronary artery disease impair interferon-γ signaling response. Nature 470:264–268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A et al (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491–1493

    Article  CAS  PubMed  Google Scholar 

  • Holdt LM, Teupser D (2012) Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol 32:196–206

    Article  CAS  PubMed  Google Scholar 

  • Holdt LM, Beutner F, Scholz M, Gielen S, Gabel G, Bergert H, Schuler G, Thiery J, Teupser D (2010) ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 30:620–627

    Article  CAS  PubMed  Google Scholar 

  • Hollander W (1976) Role of hypertension in atherosclerosis and cardiovascular disease. Am J Cardiol 38:786–800

    Article  CAS  PubMed  Google Scholar 

  • Hu WL, Li SJ, Lu DT, Wang Y, Niu SQ, Yang XC, Zhang Q, Yu SZ, Jin L, Wang XF (2009) Genetic variants on chromosome 9p21 and ischemic stroke in Chinese. Brain Res Bull 79:431–435

    Article  CAS  PubMed  Google Scholar 

  • IBC 50K CAD Consortium (2011) Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet 7:e1002260

    Article  Google Scholar 

  • Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262

    Article  CAS  PubMed  Google Scholar 

  • Johnson AD, Hwang S-J, Voorman A, Morrison A, Peloso GM, Hsu Y-H, Thanassoulis G, Newton-Cheh C, Rogers IS, Hoffmann U et al (2013) Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham Heart Study. Circulation 127:799–810

    Article  PubMed Central  PubMed  Google Scholar 

  • Jones DW, Hall JE (2004) Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure and evidence from new hypertension trials. Hypertension 43:1–3

    Article  CAS  PubMed  Google Scholar 

  • Kannel WB (1990) CHD risk factors: a Framingham study update. Hosp Pract 25:119–127

    CAS  Google Scholar 

  • Lee JY, Lee BS, Shin DJ, Woo Park K, Shin YA, Joong Kim K, Heo L, Young Lee J, Kyoung Kim Y, Jin Kim Y et al (2013) A genome-wide study of a coronary artery disease risk variant. J Hum Genet 58:120–126

    Article  CAS  PubMed  Google Scholar 

  • Lehner B (2011) Molecular mechanisms of epistasis within and between genes. Trends Genet 27:323–331

    Article  CAS  PubMed  Google Scholar 

  • Lewontin R (2002) Triple helix: gene, organism, and environment. Harvard University Press, Cambridge

    Google Scholar 

  • Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Machado DB, Crow RS, Bolan LL, Hannan PJ, Taylor HA, Folsom AR (2006) Electrocardiographic findings and incident coronary heart disease among participants in the Atherosclerosis Risk in Communities (ARIC) study. Am J Cardiol 97:1176–1181

    Article  PubMed  Google Scholar 

  • Mackay TF (2001) The genetic architecture of quantitative traits. Annu Rev Genet 35:303–339

    Article  CAS  PubMed  Google Scholar 

  • McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR et al (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488–1491

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Motterle A, Pu X, Wood H, Xiao Q, Gor S, Ng FL, Chan K, Cross F, Shohreh B, Poston RN et al (2012) Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells. Hum Mol Genet 21:4021–4029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Musunuru K (2013) Enduring mystery of the 9p21.3 locus. Circ Cardiovasc Genet 6:224–225

    Article  PubMed  Google Scholar 

  • Nägele U, Hägele EO, Sauer G, Wiedemann E, Lehmann P, Wahlefeld AW, Gruber W (1984) Reagent for the enzymatic determination of serum total triglycerides with improved lipolytic efficiency. J Clin Chem Biochem 22:165–174

    Google Scholar 

  • Nambi V, Boerwinkle E, Lawson K, Chambless L, Brautbar A, Franeschini N, North KE, Virani SS (2012) The 9p21 genetic variant is additive to carotid intima media thickness and plaque in improving coronary heart disease risk prediction in white participants of the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 222:135–137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Neel JV, Schull WJ (1954) Human heredity. University of Chicago Press, Chicago

    Google Scholar 

  • Noble D (2006) The music of life: biology beyond the genome. Oxford University Press, New York

    Google Scholar 

  • Noble D (2008) Genes and causation. Phil Trans R Soc A 366:3001–3015

    Article  CAS  PubMed  Google Scholar 

  • Palomaki GE, Melillo S, Bradley LA (2010) Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA 303:648–656

    Article  CAS  PubMed  Google Scholar 

  • Paynter NP, Chasman DI, Buring JE, Shiffman D, Cook NR, Ridker PM (2009) Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3: The Women’s Genome Health Study. Ann Intern Med 150:65–72

    Article  PubMed Central  PubMed  Google Scholar 

  • Rimoin DL, Connor JM, Pyeritz RE, Korf BR (2006) Principles and practice of medical genetics. Churchill Livingstone/Elsevier, London

    Google Scholar 

  • Roberts R, Stewart AFR (2012) 9p21 And the genetic revolution for coronary artery disease. Clin Chem 58:104–112

    Article  CAS  PubMed  Google Scholar 

  • Schiffrin EL (1998) Endothelin:role in hypertension. Biol Res 31:199–208

    CAS  PubMed  Google Scholar 

  • Schnohr P, Appleyard M, Nordestgaard BG, Jensen JS, Jensen GB, Lange P, Grønbaek M, Prescott E (2001) The Copenhagen City Heart Study. Eur Heart J Supp 3:1–83

    Article  Google Scholar 

  • Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, Preuss M, Stewart AFR, Barbalic M, Gieger C et al (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43:333–338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Scriver CR, Sly WS, Childs B, Beaudet AL, Valle D, Kinzler KW, Vogelstein B (2000) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York

    Google Scholar 

  • Shiffman D, O’Meara ES, Rowland CM, Louie JZ, Cushman M, Tracy RP, Devlin JJ, Psaty BM (2011) The contribution of a 9p21.3 variant, a KIF6 variant, and C-reactive protein to predicting risk of myocardial infarction in a prospective study. BMC Cardiovasc Disord 11:10

  • Siedel J, Hägele EO, Ziegenhorn J, Wahlefeld AW (1983) Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem 29:1075–1080

    CAS  PubMed  Google Scholar 

  • Simon A, Megnien JL, Levenson J (1997) Detection of preclinical atherosclerosis may optimize the management of hypertension. Am J Hypertens 10:813–824

    Article  CAS  PubMed  Google Scholar 

  • Sing CF, Stengård JH, Kardia SL (2003) Genes, environment, and cardiovascular disease. Arterioscler Thromb Vasc Biol 23:1190–1196

    Article  CAS  PubMed  Google Scholar 

  • Stengård JH, Frikke-Schmidt R, Tybjaerg-Hansen A, Nordestgaard BG, Sing CF (2007) Variation in 5′ promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study. Ann Hum Genet 71:762–771

    Article  PubMed Central  PubMed  Google Scholar 

  • Talmud PJ, Cooper JA, Palmen J, Lovering R, Drenos F, Hingorani AD, Humphries SE (2008) Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men. Clin Chem 54:467–474

    Article  CAS  PubMed  Google Scholar 

  • Templeton AR (2006) Population genetics and microevolutionary theory. Wiley, Hoboken

    Book  Google Scholar 

  • The ARIC Investigators (1989) The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol 129:687–702

    Google Scholar 

  • The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  PubMed Central  Google Scholar 

  • Wang X, Elston RC, Zhu X (2010) The meaning of interaction. Hum Hered 70:269–277

    Article  PubMed Central  PubMed  Google Scholar 

  • Warnick GR, Benderson J, Albers JJ (1982) Dextran sulfate–Mg2+ precipitation procedure for quantitation of high-density lipoprotein cholesterol. Clin Chem 28:1379–1388

    CAS  PubMed  Google Scholar 

  • Weiss KM, Buchanan AV (2009) The cooperative genome: organisms as social contracts. Int J Dev Biol 53:753–763

    CAS  PubMed  Google Scholar 

  • Ye S, Willeit J, Kronenberg F, Xu Q, Kiechl S (2008) 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

    Article  CAS  PubMed  Google Scholar 

  • Zeller T, Blankenberg S, Diemart P (2012) Genome-wide association studies in cardiovascular disease-an update 2011. Clin Chem 58:92–103

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank the staff and participants of the ARIC study for their important contributions. We thank Ken Weiss and Ray Lowery for managing the databases and assisting with statistical analyses and Debbie Theodore for her technical assistance in preparing this manuscript.

Funding

This work was supported by the National Institute of General Medical Sciences [P50-GM065509 to C.F.S.]; the National Heart, Lung and Blood Institute [R01-HL072905 to C.F.S., R01-HL072904 to A.G.C.,R01-HL072810 to E.B.] and the Danish Medical Research Council (01-081618).The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C].

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Human Genetics, University of Michigan, 1241 E. Catherine St., Ann Arbor, MI, 48109, USA

    Christine M. Lusk & Charles F. Sing

  2. Department of Oncology, Wayne State University, Detroit, MI, 48201, USA

    Greg Dyson

  3. Department of Molecular Biology and Genetics, Cornell University, Ithaca, USA

    Andrew G. Clark

  4. Cornell Center for Comparative and Population Genomics, Cornell University, Ithaca, NY, 14853, USA

    Andrew G. Clark

  5. Department of Medicine, Baylor College of Medicine, Houston, USA

    Christie M. Ballantyne

  6. Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, 77030, USA

    Christie M. Ballantyne

  7. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark

    Ruth Frikke-Schmidt & Anne Tybjærg-Hansen

  8. Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Ruth Frikke-Schmidt & Anne Tybjærg-Hansen

  9. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77225, USA

    Eric Boerwinkle

  10. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Eric Boerwinkle

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  1. Christine M. Lusk
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  2. Greg Dyson
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  7. Eric Boerwinkle
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  8. Charles F. Sing
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Correspondence to Charles F. Sing.

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Lusk, C.M., Dyson, G., Clark, A.G. et al. Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study. Hum Genet 133, 1105–1116 (2014). https://doi.org/10.1007/s00439-014-1451-3

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