Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
PLoS One. 2012;7(5):e37056. doi: 10.1371/journal.pone.0037056. Epub 2012 May 18.
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.
最近，针对欧洲人群的全基因组关联扫描（GWAS）和荟萃分析研究已经确定了许多先前与脂质调节相关的基因。在不同的全球人群中验证这些基因座对于确定其临床相关性很重要，特别是对于开发治疗和预防糖尿病血脂异常和冠心病（CAD）的新型药物靶点。为了在非欧洲人群中复制 GWAS 研究结果，我们研究了六个基因座（CELSR2-PSRC1-SORT1 rs599839；CDKN2A-2B rs1333049；BUD13-ZNF259 rs964184；ZNF259 rs12286037；CETP rs3764261；APOE-C1-C4-C2 rs4420638）在我们的亚洲印度人群中的作用，这些人群来自锡克教糖尿病研究（SDS），包括 3781 人（2902 人来自旁遮普邦，879 人来自美国）。在这些亚洲印度人群中，有两个被研究的六个 SNP 得到了令人信服的复制。我们的研究证实 CETP rs3764261 与高密度脂蛋白胆固醇（HDL-C）强烈相关（p=2.03×10(-26)）。我们的结果还表明，GWAS SNP（rs964184 和 rs12286037）与 BUD13-ZNF259 附近的 APOA5-A4-C3-A1 基因与该亚洲印度人群的甘油三酯（TG）水平显著相关（rs964184：p=1.74×10(-17)；rs12286037：p=1.58×10(-2)）。我们进一步在来自伦敦生命科学人群（英国）和 SDS 队列的 8530 名亚洲印度人中探索了 11q23.3 染色体区域内约 195 kb 区域内的 45 个 SNP（包括 BUD13-ZNF259、APOA5-A4-C3-A1 和 SIK3 基因）。在两个队列中，另外五个 SNP 分别与 TG 以及联合荟萃分析显示出显著相关性。然而，TG 最强的信号仍然来自 BUD13-ZNF259（rs964184：p=1.06×10(-39)）。未来的靶向深度测序和功能研究应提高我们对这些基因在血脂异常和高甘油三酯血症（HTG）以及糖尿病和 CAD 中的临床相关性的理解。
