This Article Full Text Full Text (PDF) All Versions of this Article: 38/1/41    most recent 01.STR.0000252027.53766.2bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Voetsch, B. Articles by Loscalzo, J. Search for Related Content PubMed PubMed Citation Articles by Voetsch, B. Articles by Loscalzo, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Stroke Related Collections Other Stroke Genetics of cardiovascular disease Platelets Related Article

(Stroke. 2007;38:41.)
© 2007 American Heart Association, Inc.

Original Contributions

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 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.

Correspondence to Joseph Loscalzo, MD, PhD, 77 Ave Louis Pasteur, NRB, Rm 630, Brigham and Women’s Hospital, Boston, MA 02115. 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

Related Article:

From Bench to Bedside and Back: The Value of Candidate Gene Association Studies in Translational Research

Carolyn Hoppe
Stroke 2007 38: 6. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				N. Sawada, H.-H. Kim, M. A. Moskowitz, and J. K. Liao Rac1 Is a Critical Mediator of Endothelium-Derived Neurotrophic Activity Sci. Signal., March 10, 2009; 2(61): ra10 - ra10. [Abstract] [Full Text] [PDF]

				B. Voetsch and J. Loscalzo Response to the Letter by Grond-Ginsbach et al Stroke, February 1, 2009; 40(2): e25 - e25. [Full Text] [PDF]

				S. S. Chung, M. Kim, B.-S. Youn, N. S. Lee, J. W. Park, I. K. Lee, Y. S. Lee, J. B. Kim, Y. M. Cho, H. K. Lee, et al. Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor {gamma} in Human Skeletal Muscle Cells Mol. Cell. Biol., January 1, 2009; 29(1): 20 - 30. [Abstract] [Full Text] [PDF]

				H. D. Mistry, V. Wilson, M. M. Ramsay, M. E. Symonds, and F. B. Pipkin Reduced Selenium Concentrations and Glutathione Peroxidase Activity in Preeclamptic Pregnancies Hypertension, November 1, 2008; 52(5): 881 - 888. [Abstract] [Full Text] [PDF]

				F. B. Pipkin and on behalf of The Genetics of Preeclampsia Consorti Smoking in Moderate/Severe Preeclampsia Worsens Pregnancy Outcome, but Smoking Cessation Limits the Damage Hypertension, April 1, 2008; 51(4): 1042 - 1046. [Abstract] [Full Text] [PDF]

				B. Voetsch, R. C. Jin, C. Bierl, L. Deus-Silva, E. C.S. Camargo, J. M. Annichino-Bizacchi, D. E. Handy, and J. Loscalzo Role of Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene as a Risk Factor for Cerebral Venous Thrombosis Stroke, February 1, 2008; 39(2): 303 - 307. [Abstract] [Full Text] [PDF]

				C. Hoppe From Bench to Bedside and Back: The Value of Candidate Gene Association Studies in Translational Research Stroke, January 1, 2007; 38(1): 6 - 6. [Full Text] [PDF]