Published Online
on November 22, 2006

A more recent version of this article appeared on January 1, 2007

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Submitted on July 14, 2006
Revised on August 14, 2006
Accepted on September 11, 2006

Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene. A Novel Risk Factor for Arterial Ischemic Stroke Among Young Adults and Children

Barbara Voetsch MD, PhD; Richard C. Jin BS; Charlene Bierl MD, PhD; Kelly S. Benke AB; Gili Kenet MD; Paolo Simioni MD, PhD; Filomena Ottaviano BS; Benito P. Damasceno MD, PhD; Joyce M. Annichino-Bizacchi MD, PhD; Diane E. Handy PhD; and Joseph Loscalzo MD, PhD^*

From the Whitaker Cardiovascular Institute and Evans Department of Medicine (B.V., R.C.J., C.B., F.O., D.E.H., J.L.), Boston University School of Medicine, Boston, Mass; the Department of Neurology (B.V., B.P.D., J.M.A.-B.), State University of Campinas, Brazil; the Department of Medicine, Brigham and Women’s Hospital (R.C.J., F.O., D.E.H., J.L.), Harvard Medical School, Boston, Mass; the Bloomberg School of Public Health (K.S.B.), Johns Hopkins University, Baltimore, Md; the Institute of Thrombosis and Haemostasis (G.K.), Sheba Medical Center, Israel; the Department of Medical and Surgical Sciences (P.S.), University of Padua, Italy; and the Department of Neurology (B.V.), Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: jloscalzo{at}partners.org.

Background and Purpose--Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences.

Methods--We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs.

Results--The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P=0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P=0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P<0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54±0.32 versus 2.47±0.26; P=0.0083).

Conclusion--These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the gene’s transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.

Key words: oxidative stress • platelets • thrombosis

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