文章基本信息

标题：Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project
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作者：Daniel Seung Kim ; David R. Crosslin ; Paul L. Auer 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2014
卷号：55
期号：6
页码：1173-1178
DOI：10.1194/jlr.P049247
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：HDL-associated paraoxonase-1 (PON1) is an enzyme whose activity is associated with cerebrovascular disease. Common PON1 genetic variants have not been consistently associated with cerebrovascular disease. Rare coding variation that likely alters PON1 enzyme function may be more strongly associated with stroke. The National Heart, Lung, and Blood Institute Exome Sequencing Project sequenced the coding regions (exomes) of the genome for heart, lung, and blood-related phenotypes (including ischemic stroke). In this sample of 4,204 unrelated participants, 496 had verified, noncardioembolic ischemic stroke. After filtering, 28 nonsynonymous PON1 variants were identified. Analysis with the sequence kernel association test, adjusted for covariates, identified significant associations between PON1 variants and ischemic stroke ( P = 3.01 × 10⁻³). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants ( P = 5.03 × 10⁻³). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of PON1 _Val109Ile (overall P = 7.88 × 10⁻³; AA P = 6.52 × 10⁻⁴), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identified in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted.
关键词：rare variation ; genetics ; atherosclerosis