Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
BMC Genet. 2013 May 1;14:33. doi: 10.1186/1471-2156-14-33.
High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.
A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.
We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TG）水平受基因和环境的影响。全基因组关联研究（GWAS）已经确定了~100 个与 HDL-C、LDL-C 和/或 TG 水平相关的常见遗传变异，这些变异主要存在于欧洲血统的人群中，但对于这些关联的修饰因子知之甚少。在这里，我们研究了在基因与流行病学人群结构分析（Population Architecture using Genomics and Epidemiology，PAGE）研究中，脂质特征的 GWAS 鉴定 SNP 是否存在性别异质性。
对 49 个与欧洲裔成年人空腹 HDL-C、LDL-C 和 ln（TG）水平相关的 GWAS 鉴定 SNP 进行了性别分层荟萃分析（25013 人）。当 phet < 0.001 时，确定存在性别异质性。在载脂蛋白 A1/C3/A4/A5/BUD13 基因簇中，有两个与 ln（TG）相关的 SNP 存在性别异质性：rs28927680（p(het) = 7.4×10(-7)）和 rs3135506（p(het) = 4.3×10(-4)）；在 PLTP 中，有一个与 HDL 水平相关的 SNP（rs7679；p(het) = 9.9×10(-4)），在 HMGCR 中，有一个与 LDL 水平相关的 SNP（rs12654264；p(het) = 3.1×10(-5)）。我们在先前全基因组研究报告的 17 个基因座中的 5 个中复制了性别异质性（二项式 p = 0.0009）。我们还在补充材料中提供了其他种族/民族群体的结果，为未来的荟萃分析提供了资源。
我们提供了进一步的证据表明，在 PAGE 研究中，APOA1/C3/A4/A5/BUD13 基因簇、PLTP 和 HMGCR 中的 SNP 对欧洲裔美国人空腹甘油三酯水平有性别特异性影响。我们的研究结果强调了在解释 GWAS 中出现的遗传关联时需要考虑特定背景的影响，同时也突出了在不同研究和不同种族/民族群体中复制交互作用的困难。
