Abstract
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.
Highlights
Dyslipidemia, with low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), is a well established risk factor for coronary artery disease (CAD) and a significant cause of mortality in individuals with type 2 diabetes (T2D) [1]
We previously reported a strong association of rs3764261 from the promoter region of CETP gene with HDL-C in our Punjabi cohort (n = 2,431) [17]
The serum HDL-C levels increased 13% in ‘AA’ carriers over those of common ‘CC’ carriers. These results are in agreement with this ‘A’ allele being associated with raised HDL-C levels reported in previous genome-wide association scans (GWAS) and meta-analysis studies in Caucasians [13,18]
Summary
Dyslipidemia, with low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), is a well established risk factor for coronary artery disease (CAD) and a significant cause of mortality in individuals with type 2 diabetes (T2D) [1]. Recent genome-wide association scans (GWAS) and meta-analysis studies in European populations have identified common variants in many genes, including previously known loci that are potentially involved in lipid regulation [5,6,7,8]. Replication of GWAS signals in different ethnic groups is important as the frequency of the susceptible alleles at these loci may vary significantly between world populations [11]. These studies can help identify population-specific environmental factors controlling disease risk or protection associated with specific demographic and cultural histories [11]. Replication of GWAS loci associations will have more relevance in population groups with high disease burdens such as Asian Indians [12]
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