Elsevier

Atherosclerosis

Volume 158, Issue 1, September 2001, Pages 227-231
Atherosclerosis

Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers

https://doi.org/10.1016/S0021-9150(01)00420-8Get rights and content

Abstract

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase μ1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus −0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST μ1 develop progression of atherosclerosis at an increased rate.

Introduction

Differences in genotype for enzyme systems involved in the biotransformation from cigarette smoke metabolites may differentiate the risk for cardiovascular disease among smokers [1]. The glutathione S-transferase μ1 (GSTM1) polymorphism is particularly relevant, as 50% of the general Caucasian population lacks GSTM1 enzyme activity due to two deficient GSTM1 null allelles (GSTM1-0) [2]. The enzyme GSTM1 is a member of a family of transferase enzymes. These enzymes are involved in detoxifying potential atherogenic substances such as reactive oxygen species and tobacco smoke carcinogens, including the polycyclic aromatic hydrocarbons from cigarette tar, by conjugating them to glutathion [3], [4]. Several glutathione transferases can participate in metabolism of cytotoxic aldehydes produced during lipid peroxidation, such as 4-hydroxynonenal. The transferases accelerate the reactions of these aldehydes with GSH to give less toxic conjugates [5].

We hypothesize that smokers with the GSTM1-0 genotype have increased progression of atherosclerosis. This was studied among 189 male lifelong smokers who had participated in a double-blind placebo-controlled intervention trial on the effect of 400 IU vitamin E supplementation on 2-year change of the common carotid intima media thickness (CCA-IMT). CCA-IMT change was measured by B-mode ultrasound as a valid and highly reproducible marker for atherosclerosis [6], [7], [8].

Section snippets

Methods

The present study utilized data derived from a double-blind placebo controlled 2-year intervention trial among male lifelong smokers on the effect of 400 IU vitamin E on the 2-year change in the common carotid intima media thickness (CCA-IMT).

For this intervention male inhabitants born between 1919 and 1946 from Nijmegen, a city in the Netherlands, were approached using addresses obtained from the Municipal Registration Office. The recruitment period was from October 1995 to July 1996. Eligible

Results

Baseline values for CCA-IMT were higher in the group with the GSTM1 null-compared to the positive genotype (borderline significant, P=0.09) (Table 1). At baseline no significant differences were observed in age, body mass index, smoking characteristics, plasma lipids, CVD history and hypertension between the GSTM1-1 and GSTM1-0 group (Table 1). Remarkable is the non-significant higher prevalence of CVD history and the significant higher CVD medication use in the smokers with the GSTM1-0

Discussion

In this study the 2-year progression of common carotid intima media thickness (CCA-IMT) was clearly more increased for smokers with the GSTM1-0 genotype, thus lacking the detoxification enzyme glutathione S-transferase μ, compared to smokers with the GSTM1-1 genotype. Although not statistically significant, vitamin E supplementation in smokers with the GSTM1-0 type may be beneficial shown by 46% lower increase in progression of CCA-IMT.

Studies are available on GSTM1 genotype showing increased

Acknowledgements

This study was financially supported by Research Grant #94.106 of the Netherlands Heart Foundation. Vitamin analysis as well as vitamin E and placebo capsules were provided by F Hoffman La Roche Ltd., Basel. We would like to acknowledge the following persons for assistance in collecting the data and for assistance in ultrasound measurements: T. Terburg, F.H.M.W. van Rooij, H. Van Langen, M. Brok, and A. Theloose.

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