Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

Daniel Seung Kim, David R. Crosslin, Paul L. Auer, Stephanie M. Suzuki, Judit Marsillach, Amber A. Burt, Adam S. Gordon, James F. Meschia, Mike A. Nalls, Bradford B. Worrall, W. T. Longstreth, Rebecca F. Gottesman, Clement E. Furlong, Ulrike Peters, Stephen S. Rich, Deborah A. Nickerson, Gail P. Jarvik

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 verifi ed, noncardioembolic ischemic stroke. After fi ltering, 28 nonsynonymous PON1 variants were identifi ed. Analysis with the sequence kernel association test, adjusted for covariates, identifi ed signifi cant associations between PON1 variants and ischemic stroke ( P = 3.01 × 10 3 ). Stratifi ed 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 identifi ed in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted .

Original languageEnglish (US)
Pages (from-to)1173-1178
Number of pages6
JournalJournal of Lipid Research
Volume55
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • Atherosclerosis
  • Genetics
  • Rare variation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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    Kim, D. S., Crosslin, D. R., Auer, P. L., Suzuki, S. M., Marsillach, J., Burt, A. A., Gordon, A. S., Meschia, J. F., Nalls, M. A., Worrall, B. B., Longstreth, W. T., Gottesman, R. F., Furlong, C. E., Peters, U., Rich, S. S., Nickerson, D. A., & Jarvik, G. P. (2014). Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project. Journal of Lipid Research, 55(6), 1173-1178. https://doi.org/10.1194/jlr.P049247