Genetic and non-genetic predictors of 15-year survival in patients with chronic three-vessel disease (3VD) were investigated. Coronary angiography was performed on 810 subjects with symptoms of stable ischemic heart disease in 1998. The patients with 3VD were genotyped for 23 candidate polymorphisms covering the PPAR-RXR pathway, matrix metalloproteinase-2, renin-angiotensin-aldosterone system, endothelin-1, cytokine genes, MTHFR and APO E variants. Fifteen-year survival data were obtained from the national insurance registry. All data were available in the case of 150 patients with 3VD. Statistical analysis used stepwise Cox regression with dominant, recessive, or additive mode of genetic expression. Involved variables included age, sex, BMI, blood pressure, diabetes, ejection fraction, left main stenosis, previously diagnosed coronary stenosis, myocardial infarction in personal history, and coronary bypass along with polymorphisms pre-selected by log-rank tests. Out of the 23 polymorphisms, four were included in the model construction. SNP in the IL-6 gene rs1800795 (-174 G/C) has been found to be a significant predictor of survival. This SNP was in a linkage disequilibrium with rs1800797 (-597 G/A) in the same gene (D'=1.0), which was also found to constitute a significant predictor of survival when rs1800795 was not included in the model construction. Age, increased BMI, diabetes, low EF, and left main stenosis were also significant predictors in all models. Age, increased BMI, diabetes, low ejection fraction, left main stenosis, and genetic variation in the IL-6 promoter were established as significant independent risk factors for the survival of patients with three-vessel disease.

From the Department of Pathophysiology Faculty of Medicine Masaryk University Brno Czech Republic

See more in PubMed

Gersh BJ, Sliwa K, Mayosi BM, Yusuf S. Novel therapeutic concepts: the epidemic of cardiovascular disease in the developing world: global implications. Eur Heart J 2010; 31:642–648. PubMed

WHO. World Health Organization – Global atlas on CVD prevention and control. 2011; Available from: http://whqlibdoc.who.int/publications/2011/9789241564373_eng.pdf (accessed 16/03/2012).

Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013; 381:629–638. PubMed

Lopes NH, Paulitsch FdaS, Gois AF, et al. Impact of number of vessels disease on outcome of patients with stable coronary artery disease: 5-year follow-up of the Medical, Angioplasty, and bypass Surgery study (MASS). Eur J Cardiothorac Surg 2008; 33:349–354. PubMed

Lawrie GM, Morris GC, Jr, Calhoon JH, et al. Clinical results of coronary bypass in 500 patients at least 10 years after operation. Circulation 1982; 66 (Pt 2):I1–5. PubMed

van Domburg RT, Kappetein AP, Bogers AJ. The clinical outcome after coronary bypass surgery: a 30-year follow-up study. Eur Heart J 2009; 30:453–458. PubMed

Chauhan MS, Kuntz RE, Ho KL, et al. Coronary artery stenting in the aged. J Am Coll Cardiol 2001; 37:856–862. PubMed

McPherson R. From genome-wide association studies to functional genomics: new insights into cardiovascular disease. Can J Cardiol 2013; 29:23–29. PubMed

So HC, Gui AH, Cherny SS, Sham PC. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol 2011; 35:310–317. PubMed

Casas JP, Cooper J, Miller GJ, et al. Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies. Ann Hum Genet 2006; 70 (Pt 2):145–169. PubMed

Ioannidis JP, Tarone R, McLaughlin JK. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology 2011; 22:450–456. PubMed

Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361:865–872. PubMed

Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31:969–979. PubMed

Mohan MJ, Seaton T, Mitchell J, et al. The tumor necrosis factor-alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Biochemistry 2002; 41:9462–9469. PubMed

Chistiakov DA, Sobenin IA, Orekhov AN. Regulatory T cells in atherosclerosis and strategies to induce the endogenous atheroprotective immune response. Immunol Lett 2013; 151:10–22. PubMed

Kolovou GD, Anagnostopoulou KK. Apolipoprotein E polymorphism, age and coronary heart disease. Ageing Res Rev 2007; 6:94–108. PubMed

Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 1996; 14:55–61. PubMed

Sacre SM, Stannard AK, Owen JS. Apolipoprotein E (apoE) isoforms differentially induce nitric oxide production in endothelial cells. FEBS Lett 2003; 540:181–187. PubMed

Baitsch D, Bock HH, Engel T, et al. Apolipoprotein e induces antiinflammatory phenotype in macrophages. Arterioscler Thromb Vasc Biol 2011; 31:1160–1168. PubMed PMC

Nohara A, Kobayashi J, Mabuchi H. Retinoid X receptor heterodimer variants and cardiovascular risk factors. J Atheroscler Thromb 2009; 16:303–318. PubMed

Giaginis C, Klonaris C, Katsargyris A, et al. Correlation of Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) and Retinoid X Receptor-alpha (RXR-alpha) expression with clinical risk factors in patients with advanced carotid atherosclerosis. Med Sci Monit 2011; 17:Cr381–391. PubMed PMC

Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009; 205:1–8. PubMed

Back M, Ketelhuth DF, Agewall S. Matrix metalloproteinases in atherothrombosis. Prog Cardiovasc Dis 2010; 52:410–428. PubMed

Ketelhuth DF, Back M. The role of matrix metalloproteinases in atherothrombosis. Curr Atheroscler Rep 2011; 13:162–169. PubMed

Kuzuya M, Nakamura K, Sasaki T, et al. Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26:1120–1125. PubMed

Dabek J, Glogowska-Ligus J, Szadorska B. Transcription activity of MMP-2 and MMP-9 metalloproteinase genes and their tissue inhibitor (TIMP-2) in acute coronary syndrome patients. J Postgrad Med 2013; 59:115–120. PubMed

Ferrario CM, Strawn WB. Role of the renin–angiotensin–aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 2006; 98:121–128. PubMed

Giannessi D, Del Ry S, Vitale RL. The role of endothelins and their receptors in heart failure. Pharmacol Res 2001; 43:111–126. PubMed

Eldibany MM, Caprini JA. Hyperhomocysteinemia and thrombosis: an overview. Arch Pathol Lab Med 2007; 131 6:872–884. PubMed

Hegele RA, Cao H. Single nucleotide polymorphisms of RXRA encoding retinoid X receptor alpha. J Hum Genet 2001; 46:423–425. PubMed

Vasku V, Bienertova Vasku J, Pavkova Goldbergova M, Vasku A. Three retinoid X receptor gene polymorphisms in plaque psoriasis and psoriasis guttata. Dermatology 2007; 214:118–124. PubMed

Neugebauer P, Goldbergova-Pavkova M, Kala P, et al. Nuclear receptors gene polymorphisms and risk of restenosis and clinical events following coronary stenting. Vnitr Lek 2009; 55:1135–1140. PubMed

Spinarova L, Spinar J, Vasku A, et al. Genetics of humoral and cytokine activation in heart failure and its importance for risk stratification of patients. Exp Mol Pathol 2008; 84:251–255. PubMed

Vasků A, Soucek M, Goldbergová M, Vácha J. Office blood pressure, heart rate and A(−596)G interleukin-6 gene polymorphism in apparently healthy Czech middle-aged population. Physiol Res 2003; 52:291–297. PubMed

Vasku JA, Vasku A, Goldbergova M, Vasku V. Heterozygote AG variant of −596 A/G IL-6 gene polymorphism is a marker for cutaneous T-cell lymphoma (CTCL). Clin Immunol 2004; 113:256–260. PubMed

Vasku A, Goldbergova M, Izakovicova Holla L, et al. A haplotype constituted of four MMP-2 promoter polymorphisms (−1575G/A, −1306C/T, −790T/G and −735C/T) is associated with coronary triple-vessel disease. Matrix Biol 2004; 22:585–591. PubMed

Goldbergova M, Spinarova L, Spinar J, et al. Association of two angiotensinogen gene polymorphisms, M235T and G(−6)A, with chronic heart failure. Int J Cardiol 2003; 89:267–272. PubMed

Panovsky R, Vasku A, Meluzin J, et al. Association of polymorphisms of zinc metalloproteinases with clinical response to stem cell therapy. Herz 2010; 35:309–316. PubMed

Benes P, Kankova K, Muzik J, et al. Methylenetetrahydrofolate reductase polymorphism, type II diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population. Mol Genet Metab 2001; 73:188–195. PubMed

Calero O, Hortigüela R, Bullido MJ, Calero M. Apolipoprotein E genotyping method by real time PCR, a fast and cost-effective alternative to the TaqMan and FRET assays. J Neurosci Methods 2009; 183:238–240. PubMed

Machal J, Vasku A, Hlinomaz O, et al. Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012; 156:151–158. PubMed

Gaunt TR, Rodriguez S, Zapata C, Day IN. MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers. BMC Bioinformatics 2006; 7:227. PubMed PMC

Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:937–952. PubMed

Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005; 46:454–462. PubMed

Rheaume C, Leblanc ME, Poirier P. Adiposity assessment: explaining the association between obesity, hypertension and stroke. Expert Rev Cardiovasc Ther 2011; 9:1557–1564. PubMed

Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63:582–592. PubMed

Younis N, Sharma R, Soran H, et al. Glycation as an atherogenic modification of LDL. Curr Opin Lipidol 2008; 19:378–384. PubMed

Shuvaev VV, Fujii J, Kawasaki Y, et al. Glycation of apolipoprotein E impairs its binding to heparin: identification of the major glycation site. Biochim Biophys Acta 1999; 1454:296–308. PubMed

Nobecourt E, Davies MJ, Brown BE, et al. The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase. Diabetologia 2007; 50:643–653. PubMed

Hamer M, Stamatakis E. Overweight and obese cardiac patients have better prognosis despite reporting worse perceived health and more conventional risk factors. Prev Med 2013; 57:12–16. PubMed

Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006; 368:666–678. PubMed

Schooling CM, Cowling BJ, Jones HE. Selection bias in cohorts of cases. Prev Med 2013; 57:247–248. PubMed

Fan Y, Ye J, Shen F, et al. Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab 2008; 28:90–98. PubMed PMC

Schieffer B, Selle T, Hilfiker A, et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 2004; 110:3493–3500. PubMed

Xing Z, Gauldie J, Cox G, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101:311–320. PubMed PMC

Huber SA, Sakkinen P, Conze D, et al. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999; 19:2364–2367. PubMed

Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000; 148:209–214. PubMed

Hurst SM, Wilkinson TS, McLoughlin RM, et al. IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001; 14:705–714. PubMed

Ohtsuka T, Hamada M, Inoue K, et al. Relation of circulating interleukin-6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction. Clin Cardiol 2004; 27:417–420. PubMed PMC

Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008; 5:e78. PubMed PMC

Gotsman I, Stabholz A, Planer D, et al. Serum cytokine tumor necrosis factor-alpha and interleukin-6 associated with the severity of coronary artery disease: indicators of an active inflammatory burden? Isr Med Assoc J 2008; 10:494–498. PubMed

Su D, Li Z, Li X, et al. Association between serum interleukin-6 concentration and mortality in patients with coronary artery disease. Mediators Inflamm 2013; 2013:726178. PubMed PMC

Haugen E, Gan LM, Isic A, et al. Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients. Exp Clin Cardiol 2008; 13:19–24. PubMed PMC

Fisman EZ, Tenenbaum A. The ubiquitous interleukin-6: a time for reappraisal. Cardiovasc Diabetol 2010; 9:62. PubMed PMC

Schuett H, Luchtefeld M, Grothusen C, et al. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost 2009; 102:215–222. PubMed

Schuett H, Oestreich R, Waetzig GH, et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2012; 32:281–290. PubMed

Ray A, Tatter SB, May LT, Sehgal PB. Activation of the human “beta 2-interferon/hepatocyte-stimulating factor/interleukin 6” promoter by cytokines, viruses, and second messenger agonists. Proc Natl Acad Sci U S A 1988; 85:6701–6705. PubMed PMC

Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102:1369–1376. PubMed PMC

Chen Y, Pawlikowska L, Yao JS, et al. Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol 2006; 59:72–80. PubMed

Brull DJ, Montgomery HE, Sanders J, et al. Interleukin-6 gene −174 G>C and −572 G>C promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 2001; 21:1458–1463. PubMed

Smith AJ, D’Aiuto F, Palmen J, et al. Association of serum interleukin-6 concentration with a functional IL6-6331T>C polymorphism. Clin Chem 2008; 54:841–850. PubMed

Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275:18138–18144. PubMed

Muller-Steinhardt M, Ebel B, Hartel C. The impact of interleukin-6 promoter −597/−572/−174 genotype on interleukin-6 production after lipopolysaccharide stimulation. Clin Exp Immunol 2007; 147:339–345. PubMed PMC

Peluso I, Morabito G, Urban L, et al. Oxidative stress in atherosclerosis development: the central role of LDL and oxidative burst. Endocr Metab Immune Disord Drug Targets 2012; 12:351–360. PubMed

Yin YW, Li JC, Zhang M, et al. Influence of interleukin-6 gene −174G>C polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects. Gene 2013; 529:94–103. PubMed

Antonicelli R, Olivieri F, Bonafe M, et al. The interleukin-6 −174 G>C promoter polymorphism is associated with a higher risk of death after an acute coronary syndrome in male elderly patients. Int J Cardiol 2005; 103:266–271. PubMed

Aker S, Bantis C, Reis P, et al. Influence of interleukin-6 G-174C gene polymorphism on coronary artery disease, cardiovascular complications and mortality in dialysis patients. Nephrol Dial Transplant 2009; 24:2847–2851. PubMed

Niu W, Qi Y. Matrix metalloproteinase family gene polymorphisms and risk for coronary artery disease: systematic review and meta-analysis. Heart 2012; 98:1483–1491. PubMed

Gluba A, Banach M, Mikhailidis DP, Rysz J. Genetic determinants of cardiovascular disease: the renin–angiotensin–aldosterone system, paraoxonases, endothelin-1, nitric oxide synthase and adrenergic receptors. In Vivo 2009; 23:797–812. PubMed

Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 2005; 331:1053. PubMed PMC

Sarecka-Hujar B, Zak I, Krauze J. The TT genotype of the MTHFR 677C>T polymorphism increases susceptibility to premature coronary artery disease in interaction with some of the traditional risk factors. Acta Medica (Hradec Kralove) 2012; 55:172–179. PubMed

Goldbergova MP, Spinarova L, Spinar J, et al. RXRA introne polymorphism and ABO blood groups in chronic heart failure. Central Eur J Biol 2010; 5:749–756.

Wu Z, Lou Y, Jin W, et al. The C161T polymorphism in the peroxisome proliferator-activated receptor gamma gene (PPARgamma) is associated with risk of coronary artery disease: a meta-analysis. Mol Biol Rep 2013; 40:3101–3112. PubMed

Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298:1300–1311. PubMed

Keso T, Perola M, Laippala P, et al. Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men. Atherosclerosis 2001; 154:691–697. PubMed

Rodriguez-Rodriguez L, Gonzalez-Juanatey C, Palomino-Morales R, et al. TNFA −308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 2011; 216:125–130. PubMed

Szabo GV, Acsady G. Tumornecrosis-factor-alpha 308 GA polymorphism in atherosclerotic patients. Pathol Oncol Res 2011; 17:853–857. PubMed

Li W, Xu J, Wang X, et al. Lack of association between lymphotoxin-alpha, galectin-2 polymorphisms and coronary artery disease: a meta-analysis. Atherosclerosis 2010; 208:433–436. PubMed