Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol.
Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol.
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DOI：
10.1161/circgenetics.110.957563
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发表时间：
2011-04
期刊：
影响因子：
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通讯作者：
Rader DJ
中科院分区：
文献类型：
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作者：
Edmondson AC;Braund PS;Stylianou IM;Khera AV;Nelson CP;Wolfe ML;Derohannessian SL;Keating BJ;Qu L;He J;Tobin MD;Tomaszewski M;Baumert J;Klopp N;Döring A;Thorand B;Li M;Reilly MP;Koenig W;Samani NJ;Rader DJ
已知血浆高密度脂蛋白胆固醇（HDL-C）水平具有遗传性，但仅解释了遗传性的一小部分。我们使用了一个高密度基因分型阵列，该阵列包含来自HDL-C候选基因的SNP，这些候选基因是根据已知的HDL-C代谢生物学、小鼠遗传研究和人类遗传关联研究选择的。SNP选择基于标记SNP，但也包括低频非同义SNP。在一个包含HDL-C极端值的队列（病例对照，n=1733）中进行的关联分析提供了一个发现阶段，并在另外三个人群中进行了复制，以便在7，857名个体中进行总荟萃分析。我们复制了通过全基因组关联研究鉴定的大多数基因座，并在阵列上呈现。（包括ABCA 1、APOA 1/C3/A4/A5、APOB、APOE/C1/C2、CETP、CTCF-PRMT 8、FADS 1/2/3、GALNT 2、LCAT、LILRA 3、LIPC、LIPG、LPL、LRP 4、SCARB 1、TRIB 1、ZNF 664），并提供了提示在几个先前未报道的候选基因位点（包括ABCG 1、GPR 109 A/B/81、NFKB 1、PON 1/2/3/4）中存在关联的证据。有证据表明，在五个位点中存在多个独立的关联信号，包括与低频非同义变异的关联。与HDL-C相关的遗传基因座可能含有多种独立的致病变异体，通常对HDL-C表型具有相反的影响。由极端个体组成的队列可以有效地用于数量性状的病例对照发现。
Plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high density genotyping array containing SNPs from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging-SNPs but also included low-frequency nonsynonymous SNPs. Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in three additional populations for a total meta-analysis in 7,857 individuals. We replicated the majority of loci identified through genome wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664), and provide evidence suggestive of association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in five loci, including association with low frequency nonsynonymous variants. Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts composed of extreme individuals may be efficiently used in a case-control discovery of quantitative traits.