Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S]
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 w...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-06-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520352809 |
| id |
doaj-680b177e116b4db7abed08a3bfaaecca |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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, Jr. Rebecca F. Gottesman Clement E. Furlong Ulrike Peters Stephen S. Rich Deborah A. Nickerson Gail P. Jarvik |
| spellingShingle |
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, Jr. Rebecca F. Gottesman Clement E. Furlong Ulrike Peters Stephen S. Rich Deborah A. Nickerson Gail P. Jarvik Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] Journal of Lipid Research rare variation genetics atherosclerosis |
| author_facet |
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, Jr. Rebecca F. Gottesman Clement E. Furlong Ulrike Peters Stephen S. Rich Deborah A. Nickerson Gail P. Jarvik |
| author_sort |
Daniel Seung Kim |
| title |
Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] |
| title_short |
Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] |
| title_full |
Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] |
| title_fullStr |
Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] |
| title_full_unstemmed |
Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S] |
| title_sort |
rare coding variation in paraoxonase-1 is associated with ischemic stroke in the nhlbi exome sequencing project[s] |
| publisher |
Elsevier |
| series |
Journal of Lipid Research |
| issn |
0022-2275 |
| publishDate |
2014-06-01 |
| description |
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. |
| topic |
rare variation genetics atherosclerosis |
| url |
http://www.sciencedirect.com/science/article/pii/S0022227520352809 |
| work_keys_str_mv |
AT danielseungkim rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT davidrcrosslin rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT paullauer rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT stephaniemsuzuki rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT juditmarsillach rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT amberaburt rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT adamsgordon rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT jamesfmeschia rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT mikeanalls rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT bradfordbworrall rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT wtlongstrethjr rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT rebeccafgottesman rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT clementefurlong rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT ulrikepeters rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT stephensrich rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT deborahanickerson rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects AT gailpjarvik rarecodingvariationinparaoxonase1isassociatedwithischemicstrokeinthenhlbiexomesequencingprojects |
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1721504717130956800 |
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doaj-680b177e116b4db7abed08a3bfaaecca2021-04-28T05:59:41ZengElsevierJournal of Lipid Research0022-22752014-06-0155611731178Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project[S]Daniel Seung Kim0David R. Crosslin1Paul L. Auer2Stephanie M. Suzuki3Judit Marsillach4Amber A. Burt5Adam S. Gordon6James F. Meschia7Mike A. Nalls8Bradford B. Worrall9W.T. Longstreth, Jr.10Rebecca F. Gottesman11Clement E. Furlong12Ulrike Peters13Stephen S. Rich14Deborah A. Nickerson15Gail P. Jarvik16Division 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, on behalf of the NHLBI Exome Sequencing ProjectDivision 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, on behalf of the NHLBI Exome Sequencing ProjectDivision of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WA; Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WIDivision of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WADivision 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, on behalf of the NHLBI Exome Sequencing ProjectDivision of Medical Genetics, Department of Medicine University of Washington School of Medicine, Seattle, WADepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, on behalf of the NHLBI Exome Sequencing ProjectDepartment of Neurology, Mayo Clinic, Jacksonville, FLLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MDCenter 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, VADepartment of Neurology University of Washington, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WACerebrovascular Division, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MDDivision 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, on behalf of the NHLBI Exome Sequencing ProjectDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WACenter for Public Health Genomics, University of Virginia, Charlottesville, VADepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA, on behalf of the NHLBI Exome Sequencing ProjectTo whom correspondence should be addressed; 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, on behalf of the NHLBI Exome Sequencing Project; To whom correspondence should be addressedHDL-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.http://www.sciencedirect.com/science/article/pii/S0022227520352809rare variationgeneticsatherosclerosis |