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Thromb Haemost 2008; 99(05): 944-950
DOI: 10.1160/TH07-11-0686
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Polymorphisms in the IL6 gene in Asian Indian families with premature coronary artery disease – The Indian Atherosclerosis Research Study

Arindam Maitra
1   Mary & Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India
,
Jayashree Shanker
1   Mary & Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India
,
Debabrata Dash
1   Mary & Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India
,
Shibu John
2   Elizabeth & Emmanuel Kaye Bioinformatics and Statistics Unit, Thrombosis Research Institute, Bangalore, India
,
Prathima R. Sannappa
1   Mary & Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India
,
Veena S. Rao
3   Tata Proteomics & Coagulation Unit, Thrombosis Research Institute, Bangalore, India
,
Jayakumar K. Ramanna
4   Clinical Research Unit, Thrombosis Research Institute, Bangalore, India
,
Vijay V. Kakkar
5   Emeritus Professor of University of London, London, UK
6   Chairman, Thrombosis Research Institute, Bangalore, India
7   Director, Thrombosis Research Institute, London, UK
› Author AffiliationsFinancial support: The Indian Atherosclerosis Research Study and Thrombosis Research Institute, Bangalore, India were supported by Sir Dorabji Tata Trust and Garfield Weston Foundation.
Further Information

Publication History

Received 17 November 2007

Accepted after major revision 23 March 2008

Publication Date:
30 November 2017 (online)

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Summary

Inflammation plays a major role in coronary artery disease (CAD). We investigated the polymorphisms in the interleukin 6 (IL6) gene and their effect on the expression of acute-phase proteins in premature CAD in Asian Indian families. One hundred and ninety affected sibling pairs (ASPs) were genotyped for three tag single nucleotide polymorphisms (SNPs) in the IL6 gene for linkage analysis. We observed suggestive logarithm of odds (LOD) score for one SNP (rs2066992) in a subset of 62 ASPs with the age at onset less than 45 years (LOD score = 1.114, p = 0.011 in linkage analysis; pi = 0.55, p = 0.008 in identity by descent; LOD score = 1.06, p = 0.014 in quantitative trait locus for plasma levels of high sensitivity C-reactive protein, hsCRP). This was followed by sequencing of the promoter region and haplotype analysis in 46 probands and 40 controls. Five out of the eight previously reported promoter SNPs were found to be polymorphic (rs1800797, rs1800796, rs7802307, rs7802308, rs1800795). Two novel sequence variants were also found. One promoter haplotype (GGAAG) was detected with an odds ratio (OR) of 3.676 (p = 0.0017, 95% confidence interval [CI]: 1.68 – 8.045) and population attributable risk of 21.1% (95%CI: 9.2%-31.5%). The plasma levels of both hsCRP and fibrinogen exhibited significant association with these promoter SNP genotypes (p < 0.001). In conclusion, IL6 gene polymorphisms appear to be important genetic factors in premature CAD, and in the regulation of key atherogenic markers in Asian Indian families.

Keywords

Asian Indians - CAD - IL6 - CRP - fibrinogen
 

  • References

  • 1 Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999; 340: 115-126.
    CrossrefPubMedSearch in Google Scholar
  • 2 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-1143.
    CrossrefPubMedSearch in Google Scholar
  • 3 Tuomisto K, Jousilahti P, Sundvall J. et al. C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population based, prospective study. Thromb Haemost 2006; 95: 511-518.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Online Mendelian Inheritance in Man, OMIM [TM].. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University [Baltimore, MD] and National Center for Biotechnology Information. National Library of Medicine; Bethesda, MD: 07June2007. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed January 15, 2007.
  • 5 Bataille R, Klein B. C-reactive protein levels as a direct indicator of interleukin-6 levels in humans in vivo. Arthritis Rheum 1992; 35: 982-984.
    CrossrefPubMedSearch in Google Scholar
  • 6 Yudkin JS, Stehouwer CD, Emeis JJ. et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol 1999; 19: 972-978.
    CrossrefPubMedSearch in Google Scholar
  • 7 Danesh J, Wheeler J, Hirschfield G. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-1397.
    CrossrefPubMedSearch in Google Scholar
  • 8 Seino Y, Ikeda U, Ikeda M. et al. Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 1994; 6: 87-91.
    CrossrefPubMedSearch in Google Scholar
  • 9 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772.
    CrossrefPubMedSearch in Google Scholar
  • 10 Enas EA, Yusuf S, Mehta J. Prevalence of coronary artery disease in Asian Indian. Am J Cardiol 1992; 70: 945-949.
    CrossrefPubMedSearch in Google Scholar
  • 11 Rastogi T, Reddy KS, Vaz M. et al. Diet and risk of ischemic heart disease in India. Am J Clin Nutr 2004; 79: 582-592.
    CrossrefPubMedSearch in Google Scholar
  • 12 Tillin T, Dhutia H, Chambers J. et al. South Asian men have different patterns of coronary artery disease when compared with European men. Int J Cardiol. 2007
    CrossrefPubMedSearch in Google Scholar
  • 13 Deepa R, Aravind K, Mohan V. Diabetes and risk factors for coronary artery disease. Current Science 2002; 83: 1497-1505.
    PubMedSearch in Google Scholar
  • 14 Vikram NK, Misra A, Dwivedi M. et al. Correlations of C-reactive protein levels with anthropometric profile, percentage of body fat and lipids in healthy adolescents and young adults in urban North India. Atherosclerosis 2003; 168: 305-313.
    CrossrefPubMedSearch in Google Scholar
  • 15 Chambers JC, Eda S, Bassett P. et al. C-Reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites. Circulation 2001; 104: 145-150.
    CrossrefPubMedSearch in Google Scholar
  • 16 Margaglione M, Bossone A, Cappucci G. et al. The effect of interleukin-6 C/G-174 polymorphism and circulating interleukin-6 on fibrinogen plasma levels. Haematologica 2001; 86: 199-204.
    PubMedSearch in Google Scholar
  • 17 Nauck M, Winkelmann BR, Hoffmann MM. et al. The interleukin-6 G[-174]C promoter polymorphism in the LURIC cohort: no association with plasma interleukin- 6, coronary artery disease, and myocardial infarction. J Mol Med 2002; 80: 507-513.
    CrossrefPubMedSearch in Google Scholar
  • 18 Sie MPS, Sayed-Tabatabaei FA, Oei HHS. et al. Interleukin- 6 –174 G/C promoter polymorphism and risk of coronary heart disease. Arterioscler Thromb Vasc Biol 2006; 26: 212-217.
    CrossrefPubMedSearch in Google Scholar
  • 19 Kumar NK. Bioethics activities in India. East Mediterr Health J 2006; 12: S56-S65.
    PubMedSearch in Google Scholar
  • 20 Miller SA, Dykes DD, Polesby HF. A simple salting- out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
    CrossrefPubMedSearch in Google Scholar
  • 21 The International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437: 1299-1320.
    CrossrefPubMedSearch in Google Scholar
  • 22 Rivera-chavez FA, Peters-Hybki DL, Barber RC. et al. Interleukin-6 haplotypes and interleukin 6 cytokine responses. Shock 2003; 20: 218-223.
    CrossrefPubMedSearch in Google Scholar
  • 23 Hubbard TJP, Aken BL, Beal K. et al. Ensembl 2007. Nucleic Acids Res 2006; 35 (Database issue): D610-617.
    PubMedSearch in Google Scholar
  • 24 Barrett JC, Fry B, Maller J. et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2004; 21: 263-265.
    PubMedSearch in Google Scholar
  • 25 S.A.G.E.. 2006 Statistical Analysis for Genetic Epidemiology, Release 5.3. Available at: http://genepi.cwru.edu/. Accessed March 8, 2007.
    PubMedSearch in Google Scholar
  • 26 Abecasis GR, Cherny SS, Cookson WO. et al. Merlin- rapid analysis of dense genetic maps using sparse gene-flow trees. Nat Genet 2002; 30: 97-101.
    CrossrefPubMedSearch in Google Scholar
  • 27 Hauser ER, Watanabe RM, Duren WL. et al. Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 2004; 27: 53-63.
    CrossrefPubMedSearch in Google Scholar
  • 28 Ferrari SL, Ahn-Luong L, Garnero P. et al. Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 2003; 88: 255-259.
    CrossrefPubMedSearch in Google Scholar
  • 29 Libra M, Signorelli SS, Bevelacqua Y. et al. Analysis of G[-174]C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease. J Clin Pathol 2006; 59: 211-215.
    CrossrefPubMedSearch in Google Scholar
  • 30 Paik JK, Kim OY, Koh SJ. et al. Additive effect of interleukin-6 and C-reactive protein [CRP] single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors. Clin Chim Acta 2007; 380: 68-74.
    CrossrefPubMedSearch in Google Scholar
  • 31 Lieb W, Pavlik R, Erdmann J. et al. No association of interleukin-6 gene polymorphism (- 174 G/C) with myocardial infarction or traditional cardiovascular risk factors. Int J Cardiol 2004; 97: 205-212.
    CrossrefPubMedSearch in Google Scholar
  • 32 Mälarstig A, Wallentin L, Siegbahn A. Genetic variation in the interleukin-6 gene in relation to risk and outcomes in acute coronary syndrome. Thromb Res 2007; 119: 467-473.
    CrossrefPubMedSearch in Google Scholar
  • 33 Freedman ML, Reich D, Penny KL. et al. Assessing the impact of population stratification on genetic association studies. Nat Genet 2004; 36: 388-393.
    CrossrefPubMedSearch in Google Scholar
  • 34 Zhao H, Pfeiffer R, Gail MH. Haplotype analysis in population genetics and association studies. Pharmacogenomics 2003; 4: 171-178.
    CrossrefPubMedSearch in Google Scholar
  • 35 Misra A. C-reactive protein in young individuals: problems and implications for Asian Indians. Nutrition 2004; 20: 478-481.
    CrossrefPubMedSearch in Google Scholar
  • 36 Hauser ER, Mooser V, Crossman DC. et al. Design of the Genetics of Early Onset Cardiovascular Disease (GENECARD) Study. Am Heart J 2003; 145: 602-613.
    CrossrefPubMedSearch in Google Scholar
  • 37 Pantsulaia I, Trofimov S, Kobylianski E. et al. Genetic and environmental influences on IL6 and TNF-a plasma levels in apparently healthy general population. Cytokine 2002; 19: 138-146.
    CrossrefPubMedSearch in Google Scholar
  • 38 Arnaud C, Burger F, Sabine S. et al. Statins reduce interleukin-6–induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. Arterioscler Thromb Vasc Biol 2005; 25: 1231-1236.
    CrossrefPubMedSearch in Google Scholar
  • 39 Indian Genome Variation Consortium. The Indian Genome Variation database [IGVdb]: a project overview. Hum Genet 2005; 118: 1-11.
    CrossrefPubMedSearch in Google Scholar
  • 40 Vickers MA, Green FR, Terry C. et al. Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res 2002; 53: 1029-1034.
    CrossrefPubMedSearch in Google Scholar
  • 41 Wong LY, Leung RY, Ong KL. et al. Plasma levels of fibrinogen and C-reactive protein are related to interleukin- 6 gene –572C>G polymorphism in subjects with and without hypertension. J Hum Hypertens 2007; 21: 875-882.
    CrossrefPubMedSearch in Google Scholar
  • 42 Meier-Ewert HK, Ridker PM, Rifai N. et al. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem 2001; 47: 426-430.
    PubMedSearch in Google Scholar
  • 43 Sothern RB, Roitman-Johnson B, Kanabrocki EL. et al. Circadian characteristics of circulating interleukin- 6 in men. J Allergy Clin Immunol 1995; 95: 1029-1035.
    CrossrefPubMedSearch in Google Scholar
  • 44 Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin-6 [IL6] transcriptional regulation. J Biol Chem 2000; 275: 18138-18144.
    CrossrefPubMedSearch in Google Scholar
  • 45 Noto D, Cottone S, Baldassare Cefalù A. et al. Interleukin 6 plasma levels predict with high sensitivity and specificity coronary stenosis detected by coronary angiography. Thromb Haemost 2007; 98: 1362-1367.
    Thieme ConnectPubMedSearch in Google Scholar
  • 46 Ridker PM, Hennekens CH, Buring JE. et al. C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843.
    CrossrefPubMedSearch in Google Scholar
  • 47 Miller RG. Simultaneous statistical inference.. 2nd ed. Springer Verlag; New York: 1981: 6-8.
  • 48 Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7: 781-791.
    CrossrefPubMedSearch in Google Scholar