title: Genetic determinants of clinical heterogeneity of the coronary artery disease in the population of Hyderabad, India.
abstract: Genetic predisposition to the clinical categories of coronary artery disease (anatomical viz., insignificant, single, double, and triple vessel diseases and phenotypic severity categories viz., angina, acute coronary syndrome, and myocardial infarction) is poorly understood. Particularly, the apolipoprotein genes clustered at 11q23.3 chromosomal region play a vital role in cholesterol homeostasis, and a large number of SNPs identified in this region need to be explored for their association with the clinical categories of CAD.
  
  
  
  Using fluidigm SNP genotyping platform, a prioritized set of 96 SNPs of 11q23.3 chromosomal region were genotyped on 508 CAD cases and 516 ethnicity matched controls, enrolled from Hyderabad, India, and its vicinity.
  
  
  
  The association analysis suggests 19 and 15 SNPs to be significantly associated (p ≤ 0.05) with at least one of the anatomical and/or phenotypic severity categories, respectively. Overall, the six SNPs rs17440396:G>A, rs6589566:A>G, rs2849165:G>A, rs10488699:G>A, rs1263163:G>A, and rs1263171:G>A were significant even after correction for multiple testing. Three of these (rs17440396:G>A, rs6589566:A>G, and rs2849165:G>A) that belong to BUD13, ZPR1, and APOA5-APOA4 intergenic regions, respectively, were found to be associated across the anatomical categories of CAD. However, no particular trend in the genotypic odds ratios with the increasing severity was apparent. The association analysis of the variants with phenotypic severity categories suggests that a high degree of phenotypic severity could be a result of more number of risk alleles. While the risk score analysis suggests high discriminative power of the variants towards the individual clinical categories of CAD, the complex network of interactions seen between the intronic variants of BUD13 and ZPR1 regulatory genes and intergenic variants of APOA5-APOA4 suggests pleiotropic effects of regulatory genes in the manifestation of these CAD categories.
  
  
  
  The complex network of interactions observed in the present study between the regulatory and protein-coding genes suggests their role in the manifestation of distinct clinical categories of CAD, which needs to be functionally validated.
authors.affiliation: Molecular Anthropology Group, Biological Anthropology Unit, Indian Statistical Institute, Hyderabad, India.
authors.forename: Rayabarapu
authors.initials: R
authors.lastname: Pranavchand
authors.affiliation: Department of Cardiology, Care Hospitals, Banjara Hills, Hyderabad, India.
authors.forename: Arramraju Sreenivas
authors.initials: AS
authors.lastname: Kumar
authors.affiliation: Molecular Anthropology Group, Biological Anthropology Unit, Indian Statistical Institute, Hyderabad, India. bmrisi@gmail.com.
authors.forename: Battini Mohan
authors.initials: BM
authors.lastname: Reddy
mesh_terms: D001053:Apolipoproteins / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002880:Chromosomes, Human, Pair 11; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India; D008074:Lipoproteins / Q000097:blood; D020641:Polymorphism, Single Nucleotide
chemical_list: D001053:Apolipoproteins; D008074:Lipoproteins; D002784:Cholesterol
keywords: Clinical heterogeneity; Coronary artery disease; Epistasis; Genetic association; Pleiotropy