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

Chia Ti Tsai, Juey Jen Hwang, Marylyn D. Ritchie, Jason H. Moore, Fu Tien Chiang, Ling Ping Lai, Kuan Lih Hsu, Chuen Den Tseng, Jiunn Lee Lin, Yung Zu Tseng

Research output: Contribution to journalArticle

73 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)172-180
Number of pages9
JournalAtherosclerosis
Volume195
Issue number1
DOIs
Publication statusPublished - Nov 1 2007
Externally publishedYes

Fingerprint

Gene Order
Renin-Angiotensin System
Coronary Artery Disease
Genes
Angiotensinogen
Insertional Mutagenesis
Gene Deletion
Haplotypes
Multifactor Dimensionality Reduction
Myocardial Infarction
Genotype
Angiotensin I
Angiotensin Receptors
Population Control
Peptidyl-Dipeptidase A
Cardiac Catheterization

Keywords

  • Acute myocardial infarction
  • Coronary artery disease
  • Genetics
  • Genotype disequilibrium
  • Haplotype
  • Multifactor dimensionality reduction
  • Multilocus
  • Polymorphism
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort : Detection of high order gene-gene interaction. / Tsai, Chia Ti; Hwang, Juey Jen; Ritchie, Marylyn D.; Moore, Jason H.; Chiang, Fu Tien; Lai, Ling Ping; Hsu, Kuan Lih; Tseng, Chuen Den; Lin, Jiunn Lee; Tseng, Yung Zu.

In: Atherosclerosis, Vol. 195, No. 1, 01.11.2007, p. 172-180.

Research output: Contribution to journalArticle

Tsai, Chia Ti ; Hwang, Juey Jen ; Ritchie, Marylyn D. ; Moore, Jason H. ; Chiang, Fu Tien ; Lai, Ling Ping ; Hsu, Kuan Lih ; Tseng, Chuen Den ; Lin, Jiunn Lee ; Tseng, Yung Zu. / Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort : Detection of high order gene-gene interaction. In: Atherosclerosis. 2007 ; Vol. 195, No. 1. pp. 172-180.
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