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

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.

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

“…China were reported to develop severe hypertriglyceridemia with mean TG levels of 25.89 ± 5.05 mmol/l ( 29 ). The rare allele at SNP site rs964184 ( ZNF259 ) has been reported to be associated with TG in both European and Asian populations ( 8,11,16 ). The MAF of rs964184 in the Korean population is 0.218, while it is less than 1% in Caucasians (supplementary Table 4).…”

“…ApoA5 and ZNF259 are the most probable genes hosting these variants. Studies involving people of different ancestries indicate that variants on ApoA5 and ZNF259 (rs651821, rs2075291, and rs964184) are associated with plasma TG levels ( 6,16,24,28 ). Particularly, rs2075291 ( ApoA5 ) is a nonsynonymous mutation in the coding region (Gly185Cys) mainly found in Asian populations.…”

“…Within the 11q23.3 region, we focused on chromosome 11:116,600,001-117,100,000 where previous GWAS fi ndings were localized ( 16,17,23,24 ). In order to identify the independent effects of candidate loci on TG, we used the following methods.…”

Efficient Multiple-Trait Association and Estimation of Genetic Correlation Using the Matrix-Variate Linear Mixed Model

“…For example, in the analysis of TG with CRP, we identify a SNP (rs2000571) with a P-value of 8.58e-7 and with the MTMM a P-value of 1.7e-6. This SNP was not significant in the marginal analysis of TG (1.7e-5) or CRP (0.03), but belongs to a region on chromosome 11 that has been shown to harbor variants contributing to triglycerides (Braun et al 2012). Many of the identified associated SNPs were more significant in the mvLMM compared to the MTMM, which we suspect is because the mvLMM finds the actual parameters that maximize the likelihood.…”

Multivariate Quantitative Multifactor Dimensionality Reduction for Detecting Gene-Gene Interactions

“…Apolipoprotein (APOB; rs12994068) is one of the major components related to the lipid metabolism [28] . Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2; rs4970834) is associated with dyslipidemia in the Asian Indian population [29] . Although Ca 2+ /calmodulin-dependent protein kinase-I-gamma (CAMK1G; rs10746420) is associated with lipid-raft in dendritogenesis [30] , the relationship between CAMK1G and the lipid metabolism has not been fully analyzed.…”