Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project.
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.
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Daniel Seung
DS
Kim
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
David R
DR
Crosslin
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI.
Paul L
PL
Auer
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA.
Stephanie M
SM
Suzuki
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Judit
J
Marsillach
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA.
Amber A
AA
Burt
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Adam S
AS
Gordon
Department of Neurology, Mayo Clinic, Jacksonville, FL.
James F
JF
Meschia
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
Mike A
MA
Nalls
Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Neurology, University of Virginia, Charlottesville, VA Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
Bradford B
BB
Worrall
Department of Neurology University of Washington, Seattle, WA Department of Epidemiology, University of Washington, Seattle, WA.
W T
WT
Longstreth
Cerebrovascular Division, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
Rebecca F
RF
Gottesman
Division of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Clement E
CE
Furlong
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA Department of Epidemiology, University of Washington, Seattle, WA.
Ulrike
U
Peters
Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
Stephen S
SS
Rich
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Deborah A
DA
Nickerson
Gail P
GP
Jarvik
D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D044383:Black People / Q000235:genetics; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics*; D059472:Exome; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020521:Stroke / Q000201:enzymology / Q000235:genetics*
D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
atherosclerosis; genetics; rare variation