Pirim Dilek, Wang Xingbin, Radwan Zaheda H, Niemsiri Vipavee, Bunker Clareann H, Barmada M Michael, Kamboh M Ilyas, Demirci F Yesim
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
1] Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Eur J Hum Genet. 2015 Sep;23(9):1244-53. doi: 10.1038/ejhg.2014.268. Epub 2015 Jan 28.
Genome-wide association studies have identified several loci associated with plasma lipid levels but those common variants together account only for a small proportion of the genetic variance of lipid traits. It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes. Here, we have comprehensively investigated the associations of both common and uncommon/rare variants in the lipoprotein lipase (LPL) gene in relation to plasma lipoprotein-lipid levels in African Blacks (ABs). For variant discovery purposes, the entire LPL gene and flanking regions were resequenced in 95 ABs with extreme high-density lipoprotein cholesterol (HDL-C) levels. A total of 308 variants were identified, of which 64 were novel. Selected common tagSNPs and uncommon/rare variants were genotyped in the entire sample (n=788), and 126 QC-passed variants were evaluated for their associations with lipoprotein-lipid levels by using single-site, haplotype and rare variant (SKAT-O) association analyses. We found eight not highly correlated (r(2)<0.40) signals (rs1801177:G>A, rs8176337:G>C, rs74304285:G>A, rs252:delA, rs316:C>A, rs329:A>G, rs12679834:T>C, and rs4921684:C>T) nominally (P<0.05) associated with lipid traits (HDL-C, LDL-C, ApoA1 or ApoB levels) in our sample. The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012). For TG and LDL-C, the haplotype analysis was more informative than the single-site analysis. The SKAT-O analysis revealed that the bin (group) containing 22 rare variants with MAF≤0.01 exhibited nominal association with TG (P=0.039) and LDL-C (P=0.027). Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.
全基因组关联研究已经确定了几个与血浆脂质水平相关的基因座，但这些常见变异共同仅占脂质性状遗传变异的一小部分。据推测，剩余的遗传力可能部分由具有强效应大小的罕见变异来解释。在此，我们全面研究了脂蛋白脂肪酶（LPL）基因中常见和不常见/罕见变异与非洲黑人（ABs）血浆脂蛋白-脂质水平的关联。为了发现变异，我们对95名具有极高密度脂蛋白胆固醇（HDL-C）水平的ABs个体的整个LPL基因及其侧翼区域进行了重测序。共鉴定出308个变异，其中64个是新发现的。在整个样本（n = 788）中对选定的常见标签单核苷酸多态性（tagSNPs）和不常见/罕见变异进行基因分型，并通过单位点、单倍型和罕见变异（SKAT-O）关联分析评估126个通过质量控制的变异与脂蛋白-脂质水平的关联。我们在样本中发现了8个相关性不高（r(2)<0.40）的信号（rs1801177:G>A、rs8176337:G>C、rs74304285:G>A、rs252:delA、rs316:C>A、rs329:A>G、rs12679834:T>C和rs4921684:C>T），它们与脂质性状（HDL-C、LDL-C、载脂蛋白A1或载脂蛋白B水平）名义上（P<0.05）相关。最显著的单核苷酸多态性rs252:delA与LDL-C（P = 0.002）和载脂蛋白B（P = 0.012）呈现出一种新的关联。对于甘油三酯（TG）和LDL-C，单倍型分析比单位点分析提供了更多信息。SKAT-O分析显示，包含22个次要等位基因频率（MAF）≤0.01的罕见变异的组与TG（P = 0.039）和LDL-C（P = 0.027）呈现出名义上的关联。我们的研究表明，常见和不常见/罕见的LPL变异/单倍型可能会影响一般非洲人群的血浆脂蛋白-脂质水平。
