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Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci ( CELSR2-PSRC1-SORT1  rs599839;  CDKN2A-2B  rs1333049;  BUD13-ZNF259  rs964184;  ZNF259  rs12286037;  CETP  rs3764261;  APOE-C1-C4-C2  rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of  CETP  rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10 −26 ). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from  BUD13-ZNF259  near the  APOA5-A4-C3-A1  genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10 −17 ; rs12286037: p = 1.58×10 −2 ). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the  BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3  genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with  BUD13-ZNF259  (rs964184: p = 1.06×10 −39 ). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD.

A Replication Study of GWAS-Derived Lipid Genes in Asian Indians: The Chromosomal Region 11q23.3 Harbors Loci Contributing to Triglycerides