Multi-Ethnic Analysis of Lipid-Associated Loci: The NHLBI CARe Project

BackgroundWhereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.
Methodology/Principal FindingsWe tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.
Conclusions/SignificanceWe identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

背景
既往研究已明确证实，人群血浆脂质水平具有显著的遗传力，但此前绝大多数基于欧洲裔美国人队列开展的研究中报道的遗传决定因素，在不同种族人群中的适用性仍尚不明确。
方法/主要研究结果
我们从约2000个候选基因以及全基因组关联研究（Genome-Wide Association Studies, GWAS）的遗传位点中筛选得到约50000个多态性位点，并在美国国家心、肺、血液研究所（National Heart, Lung, and Blood Institute, NHLBI）候选基因关联资源库（Candidate Gene Association Resource, CARe）的25000名欧洲裔美国人和9000名非裔美国人队列中，开展这些位点与低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL-C）以及甘油三酯（triglycerides, TG）的关联分析。我们在单个或两个种族人群中重复验证了多个基因的关联信号，并在包含细胞间黏附分子1（Intercellular Adhesion Molecule 1, ICAM1）的基因座中鉴定出一个全新的脂质相关变异位点。我们对比分析了非裔美国人和欧洲裔美国人中与脂质水平相关的遗传位点的结构特征，发现不同种族人群间关联的基因具有一致性，但每个基因对应的特异性关联变异往往存在差异。
结论/意义
本研究通过人群关联分析，鉴定或为多个血浆脂质水平的遗传决定因素提供了进一步的证据支持。在多个基因座中，非裔美国人和欧洲裔美国人群间的遗传决定因素存在显著差异。