期刊
JOURNAL OF LIPID RESEARCH
卷 55, 期 6, 页码 1173-1178出版社
ELSEVIER
DOI: 10.1194/jlr.P049247
关键词
rare variation; genetics; atherosclerosis
资金
- WA State Life Sciences Discovery Fund [265508]
- National Heart, Lung, and Blood Institute (NHLBI)
- LungGO Sequencing Project [HL-102923]
- Women's Health Initiative Sequencing Project [HL-102924]
- BroadGO Sequencing Project [HL-102925]
- SeattleGO Sequencing Project [HL-102926]
- HeartGO Sequencing Project [HL-103010]
- National Institutes of Health (NIH) [ES09883, T32ES007032]
- Intramural Research Program of the National Institute of Aging, NIH [Z01 AG-000954-06]
- Benjamin and Margaret Hall Endowed Fellowship in Genome Sciences
- Markey Foundation award
- NIH [5T31HG000035-18, 1F31MH101905-01]
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 x 10(-3)). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants (P = 5.03 x 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 x 10(-3); AA P = 6.52 x 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.
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