To further understand and interpret these findings, we performed conditional haplotype analysis by controlling for the effect of two original SNPs (rs964184 and rs12286037). As shown in the Table 8, the association of ACGCAGA haplotype with increased TG (4.62��10?6) and GACCAAC with selleck chemicals reduced TG (p=0.025) levels disappeared after including rs964184 in the model. However, the same haplotypes remained linked with increased TG (ACGCAGA, p=2.83��10?6) and reduced TG (GACCAAC, p=0.047) levels after controlling for rs12286037. These results further confirm the putative role of rs964184 for independently affecting TG concentrations. Discussion Our study has convincingly replicated the associations of two of the six most associated GWAS SNPs with blood lipid phenotypes in a non-European population.
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) . Our current data also provide strong evidence of association of rs3764261 with HDL-C in our expanded cohort (Punjabi+US) separately (Punjabi: n=2,902, ��=0.09, 6.31��10?5; US Asian Indians: n=879, ��=0.10, 1.72��10?9), and combined in a meta-analysis (n=3,781, ��=0.14, 2.03��10?26). 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 GWAS and meta-analysis studies in Caucasians , .
The other important confirmation in our findings was the robust association of TG concentrations in this cohort with rs964184 from the inter-genic region between BUD13 and ZNF259, and rs12286037 an intronic variant from ZNF259 near APOA5-A4-C3-A1. The APOA5-A4-C3-A1 locus is associated with plasma TG and VLDL-C levels in several studies including Caucasian GWAS and meta-analyses , , Chinese , Asian Indians from UK , US Whites and Blacks , and Middle-Easterns . Notably, in our study, the allelic effects of these variants were stronger under conditions of dyslipidemia associated with T2D and the difference in effect size (��=0.16 T2D vs. ��=0.10 NG control) for rs964184 was statistically significant (p=0.01). These results agree with earlier studies where the effect size of the loci contributing to quantitative traits of CAD was magnified under conditions of diabetes , .
It also was interesting to observe that not only the same risk alleles, ��G�� of rs964184 Carfilzomib (BUD13-ZNF259) and ��T�� of rs12286037 (ZNF259) were involved in raising TG levels but also the effect sizes for per ��G�� allele increase in TG was also similar in our sample (19.3 mg/dL Punjabi), (20.1 mg/dL US) and (19.3 mg/dL pooled) (Figure 3) when compared to European populations (18.12 mg/dL) . After further exploration of this region 11q23.