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Thromb Haemost 2009; 102(02): 379-388
DOI: 10.1160/TH08-01-0018
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Genetic contribution to variation in atherothrombotic phenotypes in the Asian Indian population

The Indian Atherosclerosis Research Study
Veena S. Rao
1   Tata Proteomics and Coagulation Unit, Thrombosis Research Institute, Bangalore, India
,
Natesha B. Khadrinarasimhaih
1   Tata Proteomics and Coagulation Unit, Thrombosis Research Institute, Bangalore, India
,
Saikat Kanjilal
2   Clinical Research Unit, Thrombosis Research Institute, Bangalore, India
,
Manjari Mukerjee
1   Tata Proteomics and Coagulation Unit, Thrombosis Research Institute, Bangalore, India
,
Vijay V. Kakkar
3   Narayana Hrudayalaya Hospital, Bangalore, India
4   Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, UK
› Author AffiliationsFinancial support: This study was supported by the Sir Dorabji Tata Trust and Thrombosis Research Institute, London, UK.
Further Information

Publication History

Received: 11 January 2008

Accepted after major revision: 17 May 2009

Publication Date:
22 November 2017 (online)

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Summary

Coronary artery disease (CAD) is a multifactorial disease, and family history is the best available tool to assess gene-environment interaction. This study addressed the heritability of quantitative traits, namely lipid, coagulation/fibrinolysis and pro-inflammatory markers in the ongoing family-based Indian Atherosclerosis Research Study and assessed the effect of the type/lineage of CAD family history on inheritance patterns in the highrisk Indian population. A total of 518 families comprising 2,305 individuals were recruited in phase I of the IARS; of these, 1,195 individuals from 220 families were included in the heritability analysis. With the exception of leptin, all phenotypes exhibited significant age- and sex-adjusted heritability (p<0.0001). Amongst all the phenotypes analysed after adjustment for confounding factors, the significantly higher heritability estimates of triglycerides (0.53, p<0.0001), lipoprotein (a) (0.83, p<0.0001) and interleukin-6 (0.46, p<0.0001) with low spouse pair correlations identifies them as possible CAD risk factors. Families with parental history of CAD had onset of CAD symptoms at much younger ages with significantly higher heritability of proinflammatory markers, whereas in families with sibling history of CAD, more risk factors were present at significantly higher levels. Triglycerides, lipoprotein (a) and interleukin-6 appear to be promising atherothrombotic candidate phenotypes in this population. Genes controlling these phenotypes are possible candidate genes linked with CAD. An informed understanding and incorporation of ‘family history’ as a screening tool may help in the prevention and pre-emption of CAD.

Keywords

Inflammation - SOLAR - atherosclerosis
 

  • References

  • 1 World Health Organization. World Health Statistics Annual. 2005 World Health Organization. Geneva: http://www.who.int/en/
    PubMedGoogle Scholar
  • 2 American Heart Association. Heart and Stroke statistics: 2005 Update. Dallas (TX): American Heart Association; 2005
    Google Scholar
  • 3 Donna KA. for the Writing Group. Summary of the American Heart Association’s Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease; Arterioscler. Thromb Vasc Biol 2007; 27: 1682-1686.
    CrossrefPubMedGoogle Scholar
  • 4 Farrall M, Green FR, Peden JF. et al. Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genet 2006; 02: 755-761.
    PubMedGoogle Scholar
  • 5 Scheuner MT. Review article; Clinical application of genetic risk assessment strategies for coronary artery disease: genotypes, phenotypes, and family history. Prim Care 2004; 31: 711-737.
    CrossrefPubMedGoogle Scholar
  • 6 Pohjola-Sintonen S, Rissanen A, Liskola P. et al. Family history as a risk factor of coronary heart disease in patients under 60 years of age. European Heart J 1998; 19: 235-239.
    CrossrefPubMedGoogle Scholar
  • 7 Nasir K, Michos ED, Rumberger JA. et al. Coronary artery calcification and family history of premature coronary heart disease: Sibling history is more strongly associated than parental history. Circulation 2004; 110: 2150-2156.
    CrossrefPubMedGoogle Scholar
  • 8 Kristel M, Asselt V, Kok HS. et al. Role of genetic analyses in cardiology part ii: heritability estimation for gene searching in multifactorial diseases. Circulation 2006; 113: 1136-1139.
    CrossrefPubMedGoogle Scholar
  • 9 Barrett-Connor E, Khaw K. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation 1984; 69: 1065-1069.
    CrossrefPubMedGoogle Scholar
  • 10 Executive summary of the Third Report of the National Cholesterol Education program (NCEP) Expert Panel on Detection. Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486-2497.
    CrossrefPubMedGoogle Scholar
  • 11 Murabito JM, Pencina MJ, Nam BH. et al. Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. J Am Med Assoc 2005; 294: 3117-3123.
    CrossrefPubMedGoogle Scholar
  • 12 Colditz GA, Stampfer MJ, Willett WC. et al. A prospective study of parental history of myocardial in-farction and coronary heart disease in women. Am J Epidemiol 1986; 123: 48-58.
    CrossrefPubMedGoogle Scholar
  • 13 Scheuner MT, Whitworth WC, McGruder H. et al. Expanding the definition of a positive family history for earlyonset coronary heart disease. Genet Med 2006; 08: 491-501.
    CrossrefPubMedGoogle Scholar
  • 14 Kinra S, Davey Smith G, Okasha M. et al. Is maternal transmission of coronary heart disease risk stronger than paternal transmission?. Heart 2003; 89: 834-838.
    CrossrefPubMedGoogle Scholar
  • 15 Nasir K, Budoff MJ, Wong ND. et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007; 116: 619-626.
    CrossrefPubMedGoogle Scholar
  • 16 Li R, Bensen JT, Hutchinson RG. et al. Family risk score of coronary heart disease (CHD) as a predictor of CHD: the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI Family Heart Study. Genet Epidemiol 2000; 18: 236-250.
    CrossrefPubMedGoogle Scholar
  • 17 Chadha S, Radhakrishnan S, Ramachandran K. et al. Epidemiological study of coronary heart disease in urban population of Delhi. Indian J Med Res 1992; 96: 424-430.
    PubMedGoogle Scholar
  • 18 Enas EA, Senthilkumar A. Coronary artery disease in Asian Indians: An update and review. Internet J Cardiol. 2001 vol. 1 No. 2
    PubMedGoogle Scholar
  • 19 Mission statement. 2002 American Association of Physicians of Indian Origin Coronary Artery Disease Committee. www.aapio.org
    PubMedGoogle Scholar
  • 20 Friedewald WT, Levy RI, Frederickson DL. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
    PubMedGoogle Scholar
  • 21 Expert Panel on Detection. Evaluation and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2001). J Am Med Assoc 285: 2486-2497.
    PubMedGoogle Scholar
  • 22 Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198-1211.
    CrossrefPubMedGoogle Scholar
  • 23 Enas EA. High rates of CAD in Asian Indians in the United States despite intensive modification of life style: What next?. Current Science 1998; 74: 1081-1086.
    PubMedGoogle Scholar
  • 24 Janus ED, Postiglione A, Singh RB. et al. The modernization of Asia. Implications for coronary heart disease. Council on Arteriosclerosis of the International Society and Federation of Cardiology. Circulation 1996; 94: 2671-2673.
    CrossrefPubMedGoogle Scholar
  • 25 Tillin T, Forouhi N, Johnston DG. et al. Metabolic syndrome and coronary heart disease in South Asians, African-Caribbeans and white Europeans: a UK popu-lation-based cross-sectional study. Diabetologia 2005; 48: 649-656.
    CrossrefPubMedGoogle Scholar
  • 26 Perusse L, Rice T, Despres JP. et al. Familial resemblance of plasma lipids, lipoproteins and post heparin lipoprotein and hepatic lipases in the HERITAGE Family Study. Arterioscler Thromb Vasc Biol 1997; 17: 3263-3269.
    CrossrefPubMedGoogle Scholar
  • 27 Middelberg RP, Spector TD, Swami NR. et al. Genetic and environmental influences on lipids, lipoproteins, and apolipoproteins: effects of menopause. Arterioscler Thromb Vasc Biol 2002; 22: 1142-1147.
    CrossrefPubMedGoogle Scholar
  • 28 Chien KL, Hsu HC, Su TC. et al. Consistency of genetic inheritance mode and heritability patterns of triglycerides vs. high density lipoprotein cholesterol ratio in two Taiwanese family samples. BMC Genet 2003; 04: 7.
    PubMedGoogle Scholar
  • 29 Keaney Jr. JF, Massaro JM, Larson MG. et al. Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study. J Am Coll Cardiol 2004; 44: 168-173.
    CrossrefPubMedGoogle Scholar
  • 30 Ridker PM, Buring JE, Rifai N. et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. J Am Med Assoc 2007; 297: 611-619.
    CrossrefPubMedGoogle Scholar
  • 31 Rao DC, Laskarzewski PM, Morrison JA. et al. The Cincinnati Lipid Research Clinic family study: Cultural and biological determinants of lipids and lipoprotein concentrations. Am J Hum Genet 1982; 34: 888-903.
    PubMedGoogle Scholar
  • 32 Rao DC, Morton NE, Clueck CJ. et al. Heterogeneity between populations for multifactorial inheritance of plasma lipids. Am J Hum Genet 1983; 35: 468-483.
    PubMedGoogle Scholar
  • 33 Hamsten A, Iselius L, Dahlén G. et al. Genetic and cultural inheritance of serum lipids, low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B. Atherosclerosis 1986; 60: 199-208.
    CrossrefPubMedGoogle Scholar
  • 34 Friedlander Y, Kark JD, Stein Y. Heterogeneity in multifactorial inheritance of plasma lipids and lipoproteins in ethnically diverse families in Jerusalem. Genet Epidemiol 1986; 03: 95-112.
    CrossrefPubMedGoogle Scholar
  • 35 Hunt SC, Hasstedt SJ, Kuida H. et al. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol 1989; 129: 625-638.
    CrossrefPubMedGoogle Scholar
  • 36 Rice T, Vogler GP, Perry TS. et al. Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa lipid research clinics family study. Hum Hered 1991; 41: 107-121.
    CrossrefPubMedGoogle Scholar
  • 37 Mitchell BD, Kammerer CM, Blangero J. et al. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation 1996; 94: 2159-2170.
    CrossrefPubMedGoogle Scholar
  • 38 Berg K. Role of genetic factors in atherosclerotic disease. Am J Clin Nutr 1989; 49: 1025-1029.
    CrossrefPubMedGoogle Scholar
  • 39 Hasstedt SJ, Wilson DE, Edwards CO. et al. The genetics of quantitative plasma Lp(a): analysis of a large pedigree. Am J Med Genet 1983; 16: 179-188.
    CrossrefPubMedGoogle Scholar
  • 40 Low PS, Saha N, Tay JS. et al. Ethnic variation of cord plasma apolipoprotein levels in relation to coronary risk level: a study in three ethnic groups of Singapore. Acta Paediatr 1996; 85: 1476-1482.
    CrossrefPubMedGoogle Scholar
  • 41 Anand SS, Enas EA, Pogue J. et al. Elevated lipoprotein (a) levels in South Asians in North America. Metabolism 1998; 47: 182-184.
    CrossrefPubMedGoogle Scholar
  • 42 Hultin MB. Fibrinogen and factor VII as risk factors in vascular disease. In: Coller BS. Progress in Haemostasis and Thrombosis. Philadelphia: W.B. Saunders Company; 1991: 215-241.
    Google Scholar
  • 43 Pankow JS, Folsom AR, Cushman M. et al. Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 2001; 154: 681-689.
    CrossrefPubMedGoogle Scholar
  • 44 de Maat MP, Bladbjerg EM, Hjelmborg JB. et al. Genetic influence on inflammation variables in the elderly. Arterioscler Thromb Vasc Biol 2004; 24: 2168-2173.
    CrossrefPubMedGoogle Scholar
  • 45 Peetz D, Victor A, Adams P. et al. Genetic and environmental influences on the fibrinolytic system: a twin study. Thromb Haemost 2004; 92: 344-351.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Piro M, Guibilato G, Pinelli M. et al. Endothelium and Inflammation. Panminerva Med 2005; 47: 75-80.
    PubMedGoogle Scholar
  • 47 Ma GM, Halayko AJ, Stelmack GL. et al. Effects of oxidized and glycated low-density lipoproteins on transcription and secretion of plasminogen activator inhibitor-1 in vascular endothelial cells. Cardiovasc Pathol 2006; 15: 3-10.
    CrossrefPubMedGoogle Scholar
  • 48 Iwai N, Shimoike H, Nakamura Y. et al. The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. Atherosclerosis 1998; 136: 109-114.
    CrossrefPubMedGoogle Scholar
  • 49 Isordia-Salas I, Leanos-Miranda A, Sainz IM. et al. Association of the plasminogen activator inhibitor-1 gene 4G/5G polymorphism with ST elevation acute myocardial infarction in young patients. Rev Esp Cardiol 2009; 62: 365-372.
    CrossrefPubMedGoogle Scholar
  • 50 Neil HA, Seagroatt V, Betteridge DJ. et al. Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart 2004; 90: 1431-1437.
    CrossrefPubMedGoogle Scholar
  • 51 Itakura H, Sobel BE, Boothroyd D. et al. Do plasma biomarkers of coagulation and fibrinolysis differ between patients who have experienced an acute myocardial infarction versus stable exertional angina?. Am Heart J 2007; 154: 1059-1064.
    CrossrefPubMedGoogle Scholar
  • 52 Ramachandran A, Sathyamurthy I, Snehalatha C. et al. Risk variables for coronary artery disease in Asian Indians. Am J Cardiol 2001; 87: 267-271.
    CrossrefPubMedGoogle Scholar
  • 53 Wojakowski W, Gminski J. HMG-CoA reductase inhibitors in prevention of cardiovascular diseases: new mechanisms, aspects and trials. Przegl Lek 2000; 57: 291-295.
    PubMedGoogle Scholar
  • 54 Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol 2003; 92: 18J-26J.
    PubMedGoogle Scholar
  • 55 Theuma P, Fonseca VA. Inflammation, insulin resistance, and atherosclerosis. Metab Syndr Relat Disord 2004; 02: 105-113.
    CrossrefPubMedGoogle Scholar
  • 56 Brazionis L, Rowley K, Jenkins A. et al. Plasminogen activator inhibitor-1 activity in type 2 diabetes: a different relationship with coronary heart disease and diabetic retinopathy. Arterioscler Thromb Vasc Biol 2008; 28: 786-791.
    CrossrefPubMedGoogle Scholar