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(Stroke. 2008;39:303.)
© 2008 American Heart Association, Inc.

Original Contributions

Role of Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene as a Risk Factor for Cerebral Venous Thrombosis

Barbara Voetsch, MD, PhD; Richard C. Jin, BS; Charlene Bierl, MD, PhD; Leonardo Deus-Silva, MD; Erica C.S. Camargo, MD, PhD; Joyce M. Annichino-Bizacchi, MD, PhD; Diane E. Handy, PhD Joseph Loscalzo, MD, PhD

From the Whitaker Cardiovascular Institute and Evans Department of Medicine (B.V., R.C.J., C.B., D.E.H., J.L.), Boston University School of Medicine, Boston, Mass; the Department of Medicine (D.E.H., J.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; the Department of Neurology (B.V., L.D.-S.), State University of Campinas, Brazil; the Department of Neurology (E.C.S.C.), University of São Paulo, Brazil; the Hematology and Hemotherapy Center (J.M.A.-B.), State University of Campinas, Brazil; and the Department of Neurology (B.V., E.C.S.C.), Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School.

Correspondence to Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital, Department of Medicine, 75 Francis Street, Boston, MA 02115. E-mail jloscalzo{at}partners.org

Background and Purpose— Plasma glutathione peroxidase (GPx-3) is a major antioxidant enzyme in plasma and the extracellular space that scavenges reactive oxygen species produced during normal metabolism or after oxidative insult. A deficiency of this enzyme increases extracellular oxidant stress, promotes platelet activation, and may promote oxidative posttranslational modification of fibrinogen. We recently identified a haplotype (H₂) in the GPx-3 gene promoter that increases the risk of arterial ischemic stroke among children and young adults.

Methods— The aim of this study is to identify possible relationships between promoter haplotypes in the GPx-3 gene and cerebral venous thrombosis (CVT). We studied the GPx-3 gene promoter from 23 patients with CVT and 123 young controls (18 to 45 years) by single-stranded conformational polymorphism and sequencing analysis.

Results— Over half of CVT patients (52.1%) were heterozygous (H₁H₂) or homozygous (H₂H₂) carriers of the H₂ haplotype compared with 12.2% of controls, yielding a more than 10-fold independent increase in the risk of CVT (OR=10.7; 95% CI, 2.70 to 42.36; P<0.0001). Among women, the interaction of the H₂ haplotype with hormonal risk factors increased the OR of CVT to almost 70 (P<0.0001).

Conclusions— These findings show that a novel GPx-3 promoter haplotype is a strong, independent risk factor for CVT. As we have previously shown that this haplotype is associated with a reduction in transcriptional activity, which compromises antioxidant activity and antithrombotic benefits of the enzyme, these results suggest that a deficiency of GPx-3 leads to a cerebral venous thrombophilic state.

Key Words: cerebral venous thrombosis • genetic risk factors • glutathione peroxidase • oxidant stress • thromboembolic disease