Advertisement

Renin–angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: Detection of high order gene–gene interaction

      Abstract

      There have been many reports regarding the association between renin–angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (χ2 = 31.6, P = 0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene–gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P = 0.017) and many even higher order gene–gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene–gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Taniguchi I.
        • Yamazaki T.
        • Wagatsuma K.
        • et al.
        The DD genotype of angiotensin converting enzyme polymorphism is a risk factor for coronary artery disease and coronary stent restenosis in Japanese patients.
        Jpn Circ J. 2001; 65: 897-900
        • Ko Y.L.
        • Ko Y.S.
        • Wang S.M.
        • et al.
        Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese.
        Hum Genet. 1997; 100: 210-214
        • Winkelmann B.R.
        • Russ A.P.
        • Nauck M.
        • et al.
        Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease.
        Am Heart J. 1999; 137: 698-705
        • Canavy I.
        • Henry M.
        • Morange P.E.
        • et al.
        Genetic polymorphisms and coronary artery disease in the south of France.
        Thromb Haemost. 2000; 83: 212-216
        • Jeunemaitre X.
        • Ledru F.
        • Battaglia S.
        • et al.
        Genetic polymorphisms of the renin-angiotensin system and angiographic extent and severity of coronary artery disease: the CORGENE study.
        Hum Genet. 1997; 99: 66-73
        • Martin E.R.
        • Lai E.H.
        • Gilbert J.R.
        • et al.
        SNPing away at complex disease: analysis of singe-nucleotide polymorphisms around APOE in Alzheimer disease.
        Am J Hum Genet. 2000; 67: 383-394
        • Long J.
        • Williams R.
        • Urbanek M.
        An E-M algorithm and testing strategy for multiple-locus haplotype.
        Am J Hum Genet. 1995; 56: 799-810
        • Fallin D.
        • Schork N.J.
        Accuracy of haplotype frequency estimation for biallelic loci via the expectation-maximization algorithm for unphased diploid genotype data.
        Am J Hum Genet. 2000; 67: 947-959
        • Schipper R.F.
        • D’Amaro J.
        • de Lange P.
        • et al.
        Validation of haplotype frequency estimation methods.
        Hum Immunol. 1998; 59: 518-523
        • Fallin D.
        • Cohen A.
        • Essioux L.
        • et al.
        Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer's disease.
        Genome Res. 2001; 11: 143-151
        • Ritchie M.D.
        • Hahn L.W.
        • Roodi N.
        • et al.
        Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer.
        Am J Hum Genet. 2001; 69: 138-147
        • Williams S.M.
        • Addy J.H.
        • Phillips 3rd, J.A.
        • et al.
        Combinations of variations in multiple genes are associated with hypertension.
        Hypertension. 2000; 36: 2-6
        • Tsai C.T.
        • Fallin D.
        • Chiang F.T.
        • et al.
        Angiotensinogen gene haplotype and hypertension: interaction with ACE gene I allele.
        Hypertension. 2003; 41: 9-15
        • Tsai C.T.
        • Lai L.P.
        • Lin J.L.
        • et al.
        Renin–angiotensin system gene polymorphism and atrial fibrillation.
        Circulation. 2004; 109: 1640-1646
        • Moore J.H.
        • Williams S.M.
        New strategies for identifying gene-gene interactions in hypertension.
        Ann Med. 2002; 34: 88-95
        • Moore J.H.
        • Ritchie M.D.
        The challenges of whole-genome approaches to common diseases.
        JAMA. 2004; 291: 1642-1643
      1. Lewis PO, Zaykin D. Genetic data analysis: computer program for the analysis of allelic data. Version 1.0 (d16c); 2001. Free program distributed by the authors over the internet from http://lewis.eeb.uconn.edu/lewishome/software.html.

        • Hahn L.W.
        • Ritchie M.D.
        • Moore J.H.
        Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions.
        Bioinformatics. 2003; 19: 376-382
        • Ritchie M.D.
        • Hahn L.W.
        • Moore J.H.
        Power of multifactor dimensionality reduction for detecting gene-gene and gene-environment interactions.
        Genet Epidemiol. 2003; 24: 150-157
        • Lahri D.K.
        • Nurnberger Jr., J.I.
        A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies.
        Nucl Acid Res. 1991; 19: 5444
        • Chiang F.T.
        • Lai Z.P.
        • Chern T.H.
        • et al.
        Lack of association of angiotensin converting enzyme polymorphism with essential hypertension in a Chinese population.
        Am J Hypertens. 1997; 10: 197-201
        • Chiang F.T.
        • Hsu K.L.
        • Chen W.M.
        • et al.
        Determination of angiotensin-converting enzyme gene polymorphism: stepdown PCR increases detection of heterozygotes.
        Clin Chem. 1998; 44: 1353-1356
        • Hilgers K.F.
        • Langenfeld M.R.
        • Schlaich M.
        • et al.
        1166 A/C polymorphism of the angiotensin II type 1 receptor gene and the response to short-term infusion of angiotensin II.
        Circulation. 1999; 100: 1394-1399
        • Chiang F.T.
        • Hsu K.L.
        • Tseng C.D.
        • et al.
        Molecular variant of M235T of the angiotensinogen gene is associated with essential hypertension in Taiwanese.
        J Hypertens. 1997; 15: 607-611
        • Yanai K.
        • Saito T.
        • Hirota K.
        • et al.
        Molecular variation of the human angiotensinogen core promoter element located between TATA box and transcriptional initiation site affects its transcriptional activity.
        J Biol Chem. 1997; 272: 30558-30562
        • Inoue I.
        • Nakajima T.
        • Williams C.S.
        • et al.
        A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.
        J Clin Invest. 1997; 99: 1786-1797
        • Zhao Y.Y.
        • Zhou J.
        • Narayanan C.S.
        • et al.
        Role of C/A polymorphism at −20 on the expression of human angiotensinogen gene.
        Hypertension. 1999; 33: 108-115
        • Wu S.J.
        • Chiang F.T.
        • Jiang J.R.
        • et al.
        The G-217A variant of angiotensinogen gene affects basal transcription and is associated with hypertension in a Taiwanese population.
        J Hypertens. 2003; 21: 2061-2067
      2. Stata Corporation: Stata Release 7.0 Software: statistics, data management, graphics. College Station, TX: Stata Press; 2001.

        • Williams S.M.
        • Ritchie M.D.
        • Phillips 3rd, J.A.
        • et al.
        Multilocus analysis of hypertension: a hierarchical approach.
        Hum Hered. 2004; 57: 28-38