This Article Full Text Full Text (PDF) All Versions of this Article: 111/22/2927    most recent CIRCULATIONAHA.104.509224v1 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 Doney, A. S.F. Articles by Palmer, C. N.A. Search for Related Content PubMed PubMed Citation Articles by Doney, A. S.F. Articles by Palmer, C. N.A. Related Collections Clinical genetics Acute myocardial infarction Epidemiology Genetics of cardiovascular disease Type 2 diabetes

(Circulation. 2005;111:2927-2934.)
© 2005 American Heart Association, Inc.

Epidemiology

Increased Cardiovascular Morbidity and Mortality in Type 2 Diabetes Is Associated With the Glutathione S Transferase Theta–Null Genotype

A Go-DARTS Study

Alex S.F. Doney, MRCP, PhD; Simon Lee, BSc; Graham P. Leese, FRCP, MD; Andrew D. Morris, FRCP, MD; Colin N.A. Palmer, PhD

From the Institute for Cardiovascular Research, Biomedical Research Centre (S.L., C.N.A.P.), and Department of Medicine and Therapeutics (A.S.F.D., G.P.L., A.D.M.), Ninewells Hospital and Medical School, Dundee, Scotland.

Correspondence to Colin N.A. Palmer, Biomedical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY Scotland. E-mail nuclear-receptor{at}dundee.ac.uk

Received September 27, 2004; revision received January 21, 2005; accepted February 23, 2005.

Background— Glutathione S-transferases (GSTs) modulate oxidative stress, and variation in GST genes has been associated with cardiovascular disease risk. We prospectively determined smoking-related cardiovascular morbidity by GST genotype in a large cohort of individuals with type 2 diabetes using a population-based diabetes research database (DARTS).

Methods and Results— We performed a cohort study of 2015 individuals with type 2 diabetes. Individuals were genotyped for the Ile105Val variant of GSTP1 and the deleted variants of GSTT1 and GSTM1. Clinical characteristics, smoking status, and incidence of subsequent cardiovascular events were obtained by examining the DARTS databases. Variation in the GSTP1 and GSTM1 genes was not associated with smoking-related risk of death or cardiovascular events. There was an increase in the rate of cardiovascular events in smokers lacking the GSTT1 gene compared with smokers with the GSTT1 gene intact (hazard ratio [HR], 1.96; P=0.001). This excess of cardiovascular events was due to both strokes (HR, 2.7; P=0.008) and myocardial infarctions (HR, 1.9; P=0.006). The rate of death as a result of a cardiovascular event was even more markedly increased in the GSTT1-null smokers (HR, 2.7; P=0.001), with a 2-fold increase in myocardial infarction fatality ratio. These effects translated into an increase in overall death and a decrease in age at death. We also found that the GSTT1– genotype was associated with progression of both diabetic retinopathy and nephropathy (P=0.005 and P=0.01, respectively), although we found little evidence for an interaction with smoking.

Conclusions— Genetic absence of the GSTT1 enzyme is an independent and powerful predictor of premature vascular morbidity and death in individuals with type 2 diabetes.

Key Words: death, sudden • genetics • myocardial infarction • smoking • stroke

This article has been cited by other articles:

				C. N.A. Palmer, A. S.F. Doney, S. P. Lee, I. Murrie, T. Ismail, D. F. Macgregor, and S. Mukhopadhyay Glutathione S-Transferase M1 and P1 Genotype, Passive Smoking, and Peak Expiratory Flow in Asthma Pediatrics, August 1, 2006; 118(2): 710 - 716. [Abstract] [Full Text] [PDF]