Edmondson Andrew C, Braund Peter S, Stylianou Ioannis M, Khera Amit V, Nelson Christopher P, Wolfe Megan L, Derohannessian Stephanie L, Keating Brendan J, Qu Liming, He Jing, Tobin Martin D, Tomaszewski Maciej, Baumert Jens, Klopp Norman, Döring Angela, Thorand Barbara, Li Mingyao, Reilly Muredach P, Koenig Wolfgang, Samani Nilesh J, Rader Daniel J
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
Circ Cardiovasc Genet. 2011 Apr;4(2):145-55. doi: 10.1161/CIRCGENETICS.110.957563. Epub 2011 Feb 8.
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 single-nucleotide polymorphisms (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 and 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 3 additional populations for a total meta-analysis in 7857 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 that suggests an 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 5 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 comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits.
已知血浆高密度脂蛋白胆固醇（HDL-C）水平具有遗传性，但仅能解释部分遗传力。我们使用了一种高密度基因分型阵列，其中包含基于HDL-C代谢的已知生物学、小鼠遗传学研究和人类遗传关联研究而选择的HDL-C候选基因的单核苷酸多态性（SNP）。SNP选择基于标签SNP，并包括低频非同义SNP。
在一个包含HDL-C极端值的队列（病例对照，n = 1733）中进行关联分析提供了一个发现阶段，并在另外3个群体中进行复制，以便在7857名个体中进行总计的荟萃分析。我们复制了通过全基因组关联研究鉴定并存在于阵列上的大多数位点（包括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），并提供证据表明在几个先前未报告的候选基因位点（包括ABCG1、GPR109A/B/81、NFKB1、PON1/2/3/4）存在关联。有证据表明在5个位点存在多个独立的关联信号，包括与低频非同义变体的关联。
与HDL-C相关的基因位点可能包含多个独立的致病变体，这些变体通常对HDL-C表型具有相反的影响。包含HDL-C分布极端值个体的队列可有效地用于定量性状的病例对照发现研究。
