Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project. J Lipid Res 2014 Jun;55(6):1173-8
Date
04/09/2014Pubmed ID
24711634Pubmed Central ID
PMC4031948DOI
10.1194/jlr.P049247Scopus ID
2-s2.0-84901675897 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
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 PON1Val109Ile (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.
Author List
Kim DS, Crosslin DR, Auer PL, Suzuki SM, Marsillach J, Burt AA, Gordon AS, Meschia JF, Nalls MA, Worrall BB, Longstreth WT Jr, Gottesman RF, Furlong CE, Peters U, Rich SS, Nickerson DA, Jarvik GP, NHLBI Exome Sequencing ProjectAuthor
Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AryldialkylphosphataseBrain Ischemia
Exome
Female
Genetic Variation
Humans
Male
Stroke