title: CELSR2-PSRC1-SORT1 gene expression and association with coronary artery disease and plasma lipid levels in an Asian Indian cohort.
abstract: BACKGROUND
  Genetic regulation of plasma lipids has been shown to influence the risk of coronary artery disease (CAD). We analyzed the relationship between rs599839 and rs646776 single nucleotide polymorphisms (SNPs) present in the CELSR2-PSRC1-SORT1 gene cluster, candidate gene expression, and their association with CAD and circulating lipid levels in a representative cohort of Asian Indians selected from the Indian Atherosclerosis Research Study.
  
  
  METHODS
  SNPs rs599839 and rs646776 were genotyped by Taqman assay in 1034 CAD patients (cases) and 1034 age- and gender-matched controls. Expression of CELSR2, PSRC1, and SORT1 genes was measured in 100 cases and 100 controls. Plasma levels of total cholesterol (TC), triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol (LDL-c) were measured by enzymatic assay.
  
  
  RESULTS
  Both rs646776 and rs599839 were in strong linkage disequilibrium (r = 0.98) and showed significant protective association with CAD (OR = 0.315, 95% CI 0.136-0.728, p<0.007 and OR = 0.422, 95% CI 0.181-0.981, p = 0.045, respectively). Haplotype TA showed 72% frequency and was associated with CAD (OR 0.77, 95% CI 0.67-0.88, p = 0.0002). PSRC1 gene expression was lower in the cases than in the controls (0.75 ± 0.405 versus 1.04 ± 0.622, p = 2.26 × 10(-4)). The homozygous variant and heterozygous genotypes showed 30% and 15% higher PSRC1 expression, respectively. Correspondingly, the minor alleles were associated with lower plasma TC and LDL-c levels.
  
  
  CONCLUSIONS
  PSRC1 in the cholesterol gene cluster shows a significant association with CAD by virtue of the two SNPs, rs646776 and rs599839 that also regulate plasma cholesterol levels.
authors.affiliation: Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Unit, Bangalore 560099, India.
authors.forename: Prathima
authors.initials: P
authors.lastname: Arvind
authors.affiliation: Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Unit, Bangalore 560099, India.
authors.forename: Jiny
authors.initials: J
authors.lastname: Nair
authors.affiliation: Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Unit, Bangalore 560099, India.
authors.forename: Srikarthika
authors.initials: S
authors.lastname: Jambunathan
authors.affiliation: Thrombosis Research Unit, Bangalore 560099, India; Thrombosis Research Institute, London, UK.
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Kakkar
authors.affiliation: Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Unit, Bangalore 560099, India. Electronic address: jayashreeshanker@triindia.org.in.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Shanker
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000368:Aged; D000483:Alleles; D044466:Asian People; D015820:Cadherins / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D007194:India; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015820:Cadherins; D002784:Cholesterol; D010750:Phosphoproteins; D000099183:Sortilin; C498477:CELSR2 protein, human; C485740:PSRC1 protein, human
keywords: Cholesterol gene cluster; Coronary artery disease; Plasma lipid levels; Single nucleotide polymorphism