title: Polygenetic regression model of renin-angiotensin system genes and the risk of coronary artery disease in a large angiographic population.
abstract: BACKGROUND
  Polygenetic effect has rarely been addressed in the genetic studies of coronary artery disease (CAD). We used the largest and ethnically homogeneous angiographic cohort to analyze multilocus data in renin-angiotensin system genes, and provide an explicit demonstration of gene-gene interactions.
  
  
  METHODS
  A total of 1254 consecutive patients who underwent cardiac catheterization (735 with coronary artery disease and 519 without) were recruited. Angiotensin converting enzyme(ACE) gene I/D polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects, adjust non-genetic confounding effects and detect gene-gene interaction between ACE and AT1R genes.
  
  
  RESULTS
  We found significant differences in global AGT gene haplotype profile and individual haplotypes between cases and controls. Significant two-way and three-way gene-gene interactions between ACE I/D, AT1R A1166C polymorphisms and AGT gene haplotypes were detected. However, subjects carrying both D allele and GGCATC haplotype had an increased risk of CAD (odds ratio=1.63 [1.16-2.29]; P=0.004). We also used haplotype counting to directly estimate the odds ratio of each specific AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups with different ACE or AT1R gene genotype.
  
  
  CONCLUSIONS
  The regression-based haplotype analyses permits simultaneous dectection of multi-locus and multi-gene effects in determining the risk of CAD. We provide the paradigm for genetic studies of complex-trait diseases using candidate genes based on biological pathways.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Cho-Kai
authors.initials: CK
authors.lastname: Wu
authors.forename: Jen-Kuang
authors.initials: JK
authors.lastname: Lee
authors.forename: Chuen-Den
authors.initials: CD
authors.lastname: Tseng
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wang
authors.forename: Kuan-Lih
authors.initials: KL
authors.lastname: Hsu
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Chiang
mesh_terms: D000368:Aged; D000808:Angiotensinogen / Q000235:genetics; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen