Published Online
on October 20, 2005

A more recent version of this article appeared on November 1, 2005

This Article Full Text (PDF) All Versions of this Article: 36/11/2346    most recent 01.STR.0000185703.88944.7dv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ranade, K. Articles by Dracopoli, N. C. Search for Related Content PubMed PubMed Citation Articles by Ranade, K. Articles by Dracopoli, N. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE Medline Plus Health Information Stroke Related Collections Risk Factors Genomics Genetics of Stroke Genetics of cardiovascular disease

Submitted on June 30, 2005
Revised on July 19, 2005
Accepted on July 27, 2005

Evaluation of the Paraoxonases as Candidate Genes for Stroke. Gln192Arg Polymorphism in the Paraoxonase 1 Gene Is Associated With Increased Risk of Stroke

Koustubh Ranade PhD^*; Todd G. Kirchgessner PhD; Olga A. Iakoubova PhD; James J. Devlin PhD; Terrye DelMonte BS; Priya Vishnupad BS; Lester Hui BS; Zenta Tsuchihashi PhD; Frank M. Sacks MD; Marc S. Sabatine MD, MPH; Eugene Braunwald MD; Thomas J. White PhD; Peter M. Shaw PhD; and Nicholas C. Dracopoli PhD

From the Pharmaceutical Research Institute (K.R., T.G.K., T.D., P.V., L.H., Z.T., P.M.S., N.C.D.), Bristol-Myers Squibb, Princeton, NJ; Celera Diagnostics (O.A.I., J.J.D., T.J.W.), Alameda, Calif; and Brigham & Women’s Hospital (F.M.S., M.S.S., E.B.), Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: koustubh.ranade©bms.com.

Background and Purpose--The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial.

Methods--Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes.

Results--A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (P=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (²_8df=45.58, P<0.000001). Sequence analysis of the PON1 gene from seventy stroke cases revealed a novel nonsense mutation at codon 32 in one stroke case, which was not detected in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke.

Conclusions--These results suggest that Gln192Arg genotype is an important risk factor for stroke.

Key words: association • genetics • polymorphism • stroke

This article has been cited by other articles:

				H. R. Superko Cardiovascular event risk: high-density lipoprotein and paraoxonase. J. Am. Coll. Cardiol., September 29, 2009; 54(14): 1246 - 1248. [Full Text] [PDF]

				Y.-C. Liao, H.-F. Lin, T. Rundek, R. Cheng, Y.-C. Guo, R. L. Sacco, and S.-H. H. Juo Segment-Specific Genetic Effects on Carotid Intima-Media Thickness: The Northern Manhattan Study Stroke, December 1, 2008; 39(12): 3159 - 3165. [Abstract] [Full Text] [PDF]

				S. Lavi, J. P. McConnell, R. Lavi, G. W. Barsness, C. S. Rihal, G. D. Novak, L. O. Lerman, and A. Lerman Association Between the Paraoxonase-1 192Q>R Allelic Variant and Coronary Endothelial Dysfunction in Patients With Early Coronary Artery Disease Mayo Clin. Proc., February 1, 2008; 83(2): 158 - 164. [Abstract] [Full Text] [PDF]

				M. Saeed, N. Siddique, W. Y. Hung, E. Usacheva, E. Liu, R. L. Sufit, S. L. Heller, J. L. Haines, M. Pericak-Vance, and T. Siddique Paraoxonase cluster polymorphisms are associated with sporadic ALS Neurology, September 12, 2006; 67(5): 771 - 776. [Abstract] [Full Text] [PDF]