Wang Zhe, Manichukal Ani, Goff David C, Mora Samia, Ordovas Jose M, Pajewski Nicholas M, Post Wendy S, Rotter Jerome I, Sale Michele M, Santorico Stephanie A, Siscovick David, Tsai Michael Y, Arnett Donna K, Rich Stephen, Frazier-Wood Alexis C
Department of Epidemiology, Human Genetics and Environmental Health, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA.
Hum Genet. 2017 Jun;136(6):715-726. doi: 10.1007/s00439-017-1782-y. Epub 2017 Mar 28.
A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European-Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across ethnicities with a non-European ancestry is unknown. We analyzed 15 lipoprotein subfraction measures, on 1677 African-Americans (AAs), 1450 Hispanic-Americans (HAs), and 775 Chinese-Americans (CHN) participating in the multi-ethnic study of atherosclerosis (MESA). Genome-wide data were obtained using the Affymetrix 6.0 and Illumina HumanOmni chips. Linear regression models between genetic variables and lipoprotein subfractions were adjusted for age, gender, body mass index, smoking, study center, and genetic ancestry (based on principal components), and additionally adjusted for Mexican/Non-Mexican status in HAs. A false discovery rate correction was applied separately within the results for each ethnicity to correct for multiple testing. Power calculations revealed that we did not have the power for SNP-based measures of association, so we analyzed phenotype-specific genetic risk scores (GRSs), constructed as in the original genome-wide analysis. We successfully replicated all 15 GRS-lipoprotein associations in 2527 EAs. Among the 15 significant GRS-lipoprotein associations in EAs, 11 were significant in AAs, 13 in HAs, and 1 in CHNs. Further analyses revealed that ethnicity differences could not be explained by differences in linkage disequilibrium, lipid lowering drugs, diabetes, or gender. Our study emphasizes the importance of ethnicity (here indexing genetic ancestry) in genetic risk for CVD and highlights the need to identify ethnicity-specific genetic variants associated with CVD risk.
最近一项全基因组关联研究在全基因组显著水平上，将来自43个基因组位点的62个单核苷酸多态性（SNP）与欧裔美国人（EA）的空腹脂蛋白亚组分关联起来，该研究涉及三个独立样本。这些关联在非欧洲血统的不同种族中是否一致尚不清楚。我们分析了参与动脉粥样硬化多族裔研究（MESA）的1677名非裔美国人（AA）、1450名西班牙裔美国人（HA）和775名华裔美国人（CHN）的15种脂蛋白亚组分指标。使用Affymetrix 6.0和Illumina HumanOmni芯片获取全基因组数据。遗传变量与脂蛋白亚组分之间的线性回归模型针对年龄、性别、体重指数、吸烟情况、研究中心和遗传血统（基于主成分）进行了调整，此外还针对HA中的墨西哥/非墨西哥状态进行了调整。在每个种族的结果中分别应用错误发现率校正来校正多重检验。功效计算表明，我们没有能力进行基于SNP的关联分析，因此我们分析了表型特异性遗传风险评分（GRS），其构建方式与原始全基因组分析相同。我们在2527名EA中成功复制了所有15种GRS与脂蛋白的关联。在EA中15种显著的GRS与脂蛋白关联中，11种在AA中显著，13种在HA中显著，1种在CHN中显著。进一步分析表明，种族差异无法用连锁不平衡、降脂药物、糖尿病或性别差异来解释。我们的研究强调了种族（这里指遗传血统）在心血管疾病遗传风险中的重要性，并突出了识别与心血管疾病风险相关的种族特异性遗传变异的必要性。
