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GST M1 Polymorphism Associates with DNA Oxidative Damage and Mortality among Hemodialysis Patients

Yi-Sheng Lin^*, Szu-Chun Hung, Yau-Huei Wei and Der-Cherng Tarng^,||,¶

^* Division of Nephrology, Taipei City Hospital Zhongxiao Branch, Division of Nephrology, Buddhist Tzu Chi Hospital Taipei Branch, and ^¶ Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, and Department and Institute of Physiology, ^|| Institute of Clinical Medicine, and Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

Correspondence: Dr. Der-Cherng Tarng, Department and Institute of Physiology, National Yang-Ming University and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. Phone: +886-2-2826-7080; Fax: +886-2-2826-4049; E-mail: dctarng{at}vghtpe.gov.tw

Received for publication February 25, 2008. Accepted for publication August 26, 2008.

Leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a surrogate marker of oxidant-induced DNA damage in patients undergoing maintenance hemodialysis (MHD). Glutathione S-transferase M1 (GST M1) is a member of the GST family of proteins, which protect cellular DNA against oxidative damage. This study tested the association of a common GST M1 gene polymorphism [GST M1(–)], known to produce a dysfunctional enzyme, with levels of 8-OHdG in peripheral blood leukocytes and all-cause mortality among MHD patients. Among 488 MHD patients and 372 gender-matched healthy subjects, the frequency of the GST M1(–) genotype was 63.1 and 60.2%, respectively. The GST M1(–) genotype was associated with significantly higher levels of leukocyte 8-OHdG compared with the GST M1(+) genotype, even after adjustment for potential confounders (P < 0.001). Moreover, GST M1(–) patients who also had a common polymorphism in the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 or who underwent dialysis with a bioincompatible cellulose membrane had the highest median levels of leukocyte 8-OHdG. Multivariate Cox regression revealed that among MHD patients, GST M1(–) genotype approximately doubled the risk for all-cause mortality (hazard ratio 2.24; 95% confidence interval 1.30 to 4.51) during the mean follow-up of 34 mo. In conclusion, patients without GST M1 activity are more vulnerable to oxidative stress and are at greater risk for death compared with those who possess GST M1 activity.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673