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Current Genetic Medicine Reports

, Volume 6, Issue 3, pp 116–123 | Cite as

Genetics of Subclinical Coronary Atherosclerosis

  • Lawrence F. Bielak
  • Patricia A. Peyser
Cardiovascular Genetics (B Mitchell, Section Editor)
  • 27 Downloads
Part of the following topical collections:
  1. Topical Collection on Cardiovascular Genetics

Abstract

Purpose of Review

This review highlights recent findings regarding genetics of coronary artery calcification (CAC), a marker of subclinical atherosclerosis burden, that is a precursor of clinical coronary artery disease.

Recent Findings

CAC quantity is heritable. Genome-wide association studies of common single nucleotide polymorphisms have identified genomic regions explaining ~ 2.4% of CAC heritability. Low-frequency and rare variants explain additional variation in CAC. Evidence suggests that there may be different genetic etiologies for variation in CAC progression than for cross-sectional measures of CAC. Studies integrating multiple -omics data are providing new insights into the pathobiology of subclinical coronary atherosclerosis.

Summary

The future is promising for innovative studies utilizing whole genome sequencing data as well as other -omics such as epigenomic modifications of genes and gene expression. These studies may provide multiple sources of data pointing to the same gene or pathway, thus providing greater confidence in findings.

Keywords

MESH Atherosclerosis Coronary artery disease Disease progression Genomics Epigenomics 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Bielak and Dr. Peyser report grants from NIH/NHLBI during the conduct of study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Benjamin EJ, Virani SS, Callaway CW, Chang AR, Cheng S, Chiuve SE, et al. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492.  https://doi.org/10.1161/CIR.0000000000000558.CrossRefPubMedGoogle Scholar
  2. 2.
    Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation. 2004;110:522–7.  https://doi.org/10.1161/01.CIR.0000136993.34344.41.CrossRefPubMedGoogle Scholar
  3. 3.
    Newman AB, Naydeck BL, Sutton-Tyrrell K, Edmundowicz D, O’Leary D, Kronmal R, et al. Relationship between coronary artery calcification and other measures of subclinical cardiovascular disease in older adults. Arterioscler Thromb Vasc Biol. 2002;22:1674–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Wagenknecht LE, Langefeld CD, Carr JJ, Riley W, Freedman BI, Moossavi S, et al. Race-specific relationships between coronary and carotid artery calcification and carotid intimal medial thickness. Stroke. 2004;35:e97–9.  https://doi.org/10.1161/01.STR.0000127081.99767.1d.CrossRefPubMedGoogle Scholar
  5. 5.
    • Gepner AD, Young R, Delaney JA, Tattersall MC, Blaha MJ, Post WS, et al. Comparison of coronary artery calcium presence, carotid plaque presence, and carotid intima-media thickness for cardiovascular disease prediction in the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging. 2015;8:e002262.  https://doi.org/10.1161/CIRCIMAGING.114.002262. First study to directly compare carotid plaque presence, cIMT, and CAC in a large cohort with a large number of CVD events. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bielak LF, Peyser PA, Sheedy PF 2nd. Electron-beam computed tomography screening for asymptomatic coronary artery disease. Semin Roentgenol. 2003;38:39–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–9.  https://doi.org/10.1038/362801a0.CrossRefPubMedGoogle Scholar
  8. 8.
    Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995;91:2488–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, et al. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications. A statement for health professionals from the American Heart Association. Writing Group. Circulation. 1996;94:1175–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J. 1990;11(Suppl E):3–19.CrossRefPubMedGoogle Scholar
  11. 11.
    Anderson HC. Mechanisms of pathologic calcification. Rheum Dis Clin N Am. 1988;14:303–19.Google Scholar
  12. 12.
    Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest. 1993;92:2814–20.  https://doi.org/10.1172/JCI116901.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Demer LL, Watson KE, Bostrom K. Mechanism of calcification in atherosclerosis. Trends Cardiovasc Med. 1994;4:45–9.  https://doi.org/10.1016/1050-1738(94)90025-6.CrossRefPubMedGoogle Scholar
  14. 14.
    Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest. 1994;93:2393–402.  https://doi.org/10.1172/JCI117246.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hirota S, Imakita M, Kohri K, Ito A, Morii E, Adachi S, et al. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol. 1993;143:1003–8.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Bostrom K, Watson KE, Stanford WP, Demer LL. Atherosclerotic calcification: relation to developmental osteogenesis. Am J Cardiol. 1995;75:88B–91B.CrossRefPubMedGoogle Scholar
  17. 17.
    Watson KE, Parhami F, Shin V, Demer LL. Fibronectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory. Arterioscler Thromb Vasc Biol. 1998;18:1964–71.CrossRefPubMedGoogle Scholar
  18. 18.
    Demer LL. Vascular calcification and osteoporosis: inflammatory responses to oxidized lipids. Int J Epidemiol. 2002;31:737–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Doherty TM, Detrano RC. Coronary arterial calcification as an active process: a new perspective on an old problem. Calcif Tissue Int. 1994;54:224–30.CrossRefPubMedGoogle Scholar
  20. 20.
    Hortells L, Sur S, St Hilaire C. Cell phenotype transitions in cardiovascular calcification. Front Cardiovasc Med. 2018;5:27.  https://doi.org/10.3389/fcvm.2018.00027.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Demer LL, Tintut Y. Mineral exploration: search for the mechanism of vascular calcification and beyond: the 2003 Jeffrey M. Hoeg Award lecture. Arterioscler Thromb Vasc Biol. 2003;23:1739–43.  https://doi.org/10.1161/01.ATV.0000093547.63630.0F.CrossRefPubMedGoogle Scholar
  22. 22.
    Doherty TM, Uzui H, Fitzpatrick LA, Tripathi PV, Dunstan CR, Asotra K, et al. Rationale for the role of osteoclast-like cells in arterial calcification. FASEB J. 2002;16:577–82.CrossRefPubMedGoogle Scholar
  23. 23.
    Doherty TM, Asotra K, Fitzpatrick LA, Qiao J-H, Wilkin DJ, Detrano RC, et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A. 2003;100:11201–6.  https://doi.org/10.1073/pnas.1932554100.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Doherty TM, Fitzpatrick LA, Shaheen A, Rajavashisth TB, Detrano RC. Genetic determinants of arterial calcification associated with atherosclerosis. Mayo Clin Proc. 2004;79:197–210.CrossRefPubMedGoogle Scholar
  25. 25.
    Doherty TM, Fitzpatrick LA, Inoue D, Qiao J-H, Fishbein MC, Detrano RC, et al. Molecular, endocrine, and genetic mechanisms of arterial calcification. Endocr Rev. 2004;25:629–72.  https://doi.org/10.1210/er.2003-0015.CrossRefPubMedGoogle Scholar
  26. 26.
    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995;92:2157–62.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Baumgart D, Schmermund A, Goerge G, Haude M, Ge J, Adamzik M, et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol. 1997;30:57–64.CrossRefPubMedGoogle Scholar
  29. 29.
    Bielak LF, Rumberger JA, Sheedy PF 2nd, Schwartz RS, Peyser PA. Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata. Circulation. 2000;102:380–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Budoff MJ, Shokooh S, Shavelle RM, Kim HT, French WJ. Electron beam tomography and angiography: sex differences. Am Heart J. 2002;143:877–82.  https://doi.org/10.1016/j.jcmg.2010.08.018.CrossRefPubMedGoogle Scholar
  31. 31.
    Bild DE, Detrano R, Peterson D, Guerci A, Liu K, Shahar E, et al. Ethnic differences in coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation. 2005;111:1313–20.  https://doi.org/10.1161/01.CIR.0000157730.94423.4B.CrossRefPubMedGoogle Scholar
  32. 32.
    Nasir K, Katz R, Takasu J, Shavelle DM, Detrano R, Lima JA, et al. Ethnic differences between extra-coronary measures on cardiac computed tomography: Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2008;198:104–14.  https://doi.org/10.1016/j.atherosclerosis.2007.09.008.CrossRefPubMedGoogle Scholar
  33. 33.
    Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–45.  https://doi.org/10.1056/NEJMoa072100.CrossRefPubMedGoogle Scholar
  34. 34.
    Tota-Maharaj R, Blaha MJ, Blankstein R, Silverman MG, Eng J, Shaw LJ, et al. Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the Multi-Ethnic Study of Atherosclerosis: a secondary analysis of a prospective, population-based cohort. Mayo Clin Proc. 2014;89:1350–9.  https://doi.org/10.1016/j.mayocp.2014.05.017.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    • Joshi PH, Patel B, Blaha MJ, Berry JD, Blankstein R, Budoff MJ, et al. Coronary artery calcium predicts cardiovascular events in participants with a low lifetime risk of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2016;246:367–73.  https://doi.org/10.1016/j.atherosclerosis.2016.01.017. A high CAC burden strongly predicts incident coronary heart disease events among those with a low 10-year risk of CVD. CrossRefPubMedGoogle Scholar
  36. 36.
    Hermann DM, Gronewold J, Lehmann N, Moebus S, Jockel K-H, Bauer M, et al. Coronary artery calcification is an independent stroke predictor in the general population. Stroke. 2013;44:1008–13.  https://doi.org/10.1161/STROKEAHA.111.678078.CrossRefPubMedGoogle Scholar
  37. 37.
    Leening MJ, Elias-Smale SE, Kavousi M, Felix JF, Deckers JW, Vliegenthart R, et al. Coronary calcification and the risk of heart failure in the elderly: the Rotterdam Study. JACC Cardiovascular Imaging. 2012;5:874–80.  https://doi.org/10.1016/j.jcmg.2012.03.016.CrossRefPubMedGoogle Scholar
  38. 38.
    O’Neal WT, Efird JT, Dawood FZ, Yeboah J, Alonso A, Heckbert SR, et al. Coronary artery calcium and risk of atrial fibrillation (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol. 2014;114:1707–12.  https://doi.org/10.1016/j.amjcard.2014.09.005.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Handy CE, Desai CS, Dardari ZA, Al-Mallah MH, Miedema MD, Ouyang P, et al. The association of coronary artery calcium with noncardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. JACC Cardiovasc Imaging. 2016;9:568–76.  https://doi.org/10.1016/j.jcmg.2015.09.020.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Grundy SM. Age as a risk factor: you are as old as your arteries. Am J Cardiol. 1999;A7:1455–7.Google Scholar
  41. 41.
    Peyser PA, Bielak LF, Chu JS, Turner ST, Ellsworth DL, Boerwinkle E, et al. Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults. Circulation. 2002;106:304–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Wojczynski MK, Li M, Bielak LF, Kerr KF, Reiner AP, Wong ND, et al. Genetics of coronary artery calcification among African Americans, a meta-analysis. BMC Med Genet. 2013;14(75)  https://doi.org/10.1186/1471-2350-14-75.
  43. 43.
    Shen H, Bielak LF, Ferguson JF, Streeten EA, Yerges-Armstrong LM, Liu J, et al. Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification. Arterioscler Thromb Vasc Biol. 2010;30:2648–54.  https://doi.org/10.1161/ATVBAHA.110.211805.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    O’Donnell CJ, Kavousi M, Smith AV, Kardia SLR, Feitosa MF, S-JJ H, et al. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation. 2011;124:2855–64.  https://doi.org/10.1161/CIRCULATIONAHA.110.974899.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    van Setten J, Isgum I, Smolonska J, Ripke S, de Jong PA, Oudkerk M, et al. Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction. Atherosclerosis. 2013;228:400–5.  https://doi.org/10.1016/j.atherosclerosis.2013.02.039.CrossRefPubMedGoogle Scholar
  46. 46.
    Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18:331–44.  https://doi.org/10.1038/nrg.2016.160.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    •• Beaudoin M, Gupta RM, Won H-H, Lo KS, Do R, Henderson CA, et al. Myocardial infarction-associated SNP at 6p24 interferes with MEF2 binding and associates with PHACTR1 expression levels in human coronary arteries. Arterioscler Thromb Vasc Biol. 2015;35:1472–9.  https://doi.org/10.1161/ATVBAHA.115.305534. This study provides a model and candidate tissue to investigate how PHACTR1 influences atherosclerosis. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    •• Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell. 2017;170:522–533.e15.  https://doi.org/10.1016/j.cell.2017.06.049. This study integrates genetic, epigenetic, and phenotypic data to investigate biologic mechanisms contributing to the pathogenesis of multiple vascular diseases. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhao W, Smith JA, Mao G, Fornage M, Peyser PA, Sun YV, et al. The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. BMC Med Genet. 2015;8(21):21.  https://doi.org/10.1186/s12920-015-0094-0. CrossRefGoogle Scholar
  50. 50.
    Holdt LM, Teupser D. From genotype to phenotype in human atherosclerosis—recent findings. Curr Opin Lipidol. 2013;24:410–8.  https://doi.org/10.1097/MOL.0b013e3283654e7c.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Holdt LM, Hoffmann S, Sass K, Langenberger D, Scholz M, Krohn K, et al. Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet. 2013;9:e1003588.  https://doi.org/10.1371/journal.pgen.1003588.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, et al. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016;7:12429.  https://doi.org/10.1038/ncomms12429.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Schmidt B, Frolich S, Dragano N, Frank M, Eisele L, Pechlivanis S, et al. Socioeconomic status interacts with the genetic effect of a chromosome 9p21.3 common variant to influence coronary artery calcification and incident coronary events in the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcium, and Lifestyle). Circ Cardiovasc Genet. 2017;10:e001441.  https://doi.org/10.1161/CIRCGENETICS.116.001441. CrossRefPubMedGoogle Scholar
  54. 54.
    Divers J, Palmer ND, Lu L, Register TC, Carr JJ, Hicks PJ, et al. Admixture mapping of coronary artery calcified plaque in African Americans with type 2 diabetes mellitus. Circ Cardiovasc Genet. 2013;6:97–105.  https://doi.org/10.1186/s12863-017-0572-9. CrossRefPubMedGoogle Scholar
  55. 55.
    Gomez F, Wang L, Abel H, Zhang Q, Province MA, Borecki IB. Admixture mapping of coronary artery calcification in African Americans from the NHLBI family heart study. BMC Genet. 2015;16(42):42.  https://doi.org/10.1186/s12863-015-0196-x. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    • Natarajan P, Bis JC, Bielak LF, Cox AJ, Dorr M, Feitosa MF, et al. Multiethnic exome-wide association study of subclinical atherosclerosis. Circ Cardiovasc Genet. 2016;9:511–20.  https://doi.org/10.1161/CIRCGENETICS.116.001572. Multi-ethnic exome-wide association of meta-analysis of CAC quantity and cIMT found protein-coding variants in APOE associated with subclinical atherosclerosis. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298:1300–11.  https://doi.org/10.1001/jama.298.11.1300.CrossRefPubMedGoogle Scholar
  58. 58.
    Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702–5.  https://doi.org/10.1126/science.1161524.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Shen H, Damcott CM, Rampersaud E, Pollin TI, Horenstein RB, McArdle PF, et al. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the Old Order Amish. Arch Intern Med. 2010;170:1850–5.  https://doi.org/10.1001/archinternmed.2010.384.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Neefjes LA, Ten Kate G-JR, Alexia R, Nieman K, Galema-Boers AJ, Langendonk JG, et al. Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia. Atherosclerosis. 2011;219:721–7.  https://doi.org/10.1016/j.atherosclerosis.2011.09.052.CrossRefPubMedGoogle Scholar
  61. 61.
    D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care. Circulation. 2008;117:743–53.CrossRefPubMedGoogle Scholar
  62. 62.
    Morrison AC, Bare LA, Chambless LE, Ellis SG, Malloy M, Kane JP, et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2007;166:28–35.  https://doi.org/10.1093/aje/kwm060.CrossRefPubMedGoogle Scholar
  63. 63.
    Salfati E, Nandkeolyar S, Fortmann SP, Sidney S, Hlatky MA, Quertermous T, et al. Susceptibility loci for clinical coronary artery disease and subclinical coronary atherosclerosis throughout the life-course. Circ Cardiovasc Genet. 2015;8:803–11.  https://doi.org/10.1161/CIRCGENETICS.114.001071. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Cassidy-Bushrow AE, Bielak LF, Sheedy PF 2nd, Turner ST, Kullo IJ, Lin X, et al. Coronary artery calcification progression is heritable. Circulation. 2007;116:25–31.  https://doi.org/10.1161/CIRCULATIONAHA.106.658583.CrossRefPubMedGoogle Scholar
  65. 65.
    Kretowski A, Hokanson JE, McFann K, Kinney GL, Snell-Bergeon JK, Maahs DM, et al. The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes. Diabetologia. 2006;49:1946–54.  https://doi.org/10.1007/s00125-006-0317-1.CrossRefPubMedGoogle Scholar
  66. 66.
    Kretowski A, McFann K, Hokanson JE, Maahs D, Kinney G, Snell-Bergeon JK, et al. Polymorphisms of the renin-angiotensin system genes predict progression of subclinical coronary atherosclerosis. Diabetes. 2007;56:863–71.  https://doi.org/10.2337/db06-1321.CrossRefPubMedGoogle Scholar
  67. 67.
    Cassidy-Bushrow AE, Bielak LF, Levin AM, Sheedy PF 2nd, Turner ST, Boerwinkle E, et al. Matrix gla protein gene polymorphism is associated with increased coronary artery calcification progression. Arterioscler Thromb Vasc Biol. 2013;33:645–65.  https://doi.org/10.1161/ATVBAHA.112.300491.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    •• Aherrahrou R, Aherrahrou Z, Schunkert H, Erdmann J. Coronary artery disease associated gene Phactr1 modulates severity of vascular calcification in vitro. Biochem Biophys Res Commun. 2017;491:396–402.  https://doi.org/10.1016/j.bbrc.2017.07.090. This study demonstrates that PHACTR1 gene expression increases with the progression of calcification and regulation of PHACTR1 expression modulates severity of calcification. CrossRefPubMedGoogle Scholar
  69. 69.
    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–21.  https://doi.org/10.1056/NEJMoa1701719.CrossRefPubMedGoogle Scholar
  70. 70.
    Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 2016;17:255.  https://doi.org/10.1186/s13059-016-1119-5. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat Genet. 2015;47:1282–93.  https://doi.org/10.1038/ng.3405.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Soriano-Tarraga C, Jimenez-Conde J, Giralt-Steinhauer E, Mola-Caminal M, Vivanco-Hidalgo RM, Ois A, et al. Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. Hum Mol Genet. 2016;25:609–19.  https://doi.org/10.1093/hmg/ddv493.CrossRefPubMedGoogle Scholar
  73. 73.
    Joehanes R, Just AC, Marioni RE, Pilling LC, Reynolds LM, Mandaviya PR, et al. Epigenetic signatures of cigarette smoking. Circ Cardiovasc Genet. 2016;9:436–47.  https://doi.org/10.1161/CIRCGENETICS.116.001506. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Rask-Andersen M, Martinsson D, Ahsan M, Enroth S, Ek WE, Gyllensten U, et al. Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction. Hum Mol Genet. 2016;25:4739–48.  https://doi.org/10.1093/hmg/ddw302. PubMedCrossRefGoogle Scholar
  75. 75.
    Hou L, Zheng Y, Allen NB, Nannini D, Zhang Z, Liu L, et al. Abstract P037: epigenetic markers of cardiovascular health trajectories and coronary artery calcification in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Circulation. 2017;135:AP037.Google Scholar
  76. 76.
    Sen SK, Boelte KC, Barb JJ, Joehanes R, Zhao X, Cheng Q, et al. Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am J Hum Genet. 2014;95:66–76.  https://doi.org/10.1016/j.ajhg.2014.06.003.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhao W, Lee J-J, Rasheed A, Saleheen D. Using Mendelian randomization studies to assess causality and identify new therapeutic targets in cardiovascular medicine. Curr Genet Med Rep. 2016;4:207–12.  https://doi.org/10.1007/s40142-016-0103-4.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Holmes MV, Ala-Korpela M, Smith GD. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat Rev Cardiol. 2017;14:577–90.  https://doi.org/10.1038/nrcardio.2017.78.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    VanderWeele TJ, Tchetgen Tchetgen EJ, Cornelis M, Kraft P. Methodological challenges in Mendelian randomization. Epidemiology. 2014;25:427–35.  https://doi.org/10.1097/EDE.0000000000000081.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Rao DC, Sung YJ, Winkler TW, Schwander K, Borecki I, Cupples LA, et al. Multiancestry study of gene-lifestyle interactions for cardiovascular traits in 610 475 individuals from 124 cohorts: design and rationale. Circulation: Genomic and Precision Medicine. 2017;10:e001649.  https://doi.org/10.1161/CIRCGENETICS.116.001649.CrossRefGoogle Scholar
  81. 81.
    Sung YJ, Winkler TW, de Las Fuentes L, Bentley AR, Brown MR, Kraja AT, et al. A large-scale multi-ancestry genome-wide study accounting for smoking behavior identifies multiple significant loci for blood pressure. Am J Hum Genet. 2018;102:375–400.  https://doi.org/10.1016/j.ajhg.2018.01.015.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Kavousi M, Bielak LF, Peyser PA. Genetic research and women’s heart disease: a primer. Curr Atheroscler Rep. 2016;18:67.  https://doi.org/10.1007/s11883-016-0618-x.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Epidemiology, School of Public HealthUniversity of MichiganAnn ArborUSA

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