Abstract

BackgroundGlutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. Methods and FindingsLiterature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively. ConclusionsThe risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.

Highlights

  • Glutathione S-transferases (GSTs, Enzyme Commission 2.5.1.18) are a large family of cytosolic enzymes that catalyze the detoxification of reactive electrophilic compounds, including many environmental carcinogens [1,2]

  • Data Searching Genetic association studies published before August, 2005, investigating at least one of the five polymorphisms in the GST genes described above and lung cancer risk were sought by computer-based searches, scanning of the reference lists for all relevant studies and review articles, hand searching of relevant journals, and correspondence with authors of included studies

  • Computer searches of PubMed, Web of Science, EMBASE, and CNKI used keywords relating to the relevant genes (e.g., ‘‘GSTT1,’’ ‘‘GSTP1,’’ ‘‘GSTM3,’’ and ‘‘glutathione Stransferase’’) in combination with words related to lung cancer or lung-neoplasms without language restriction

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Summary

Introduction

Glutathione S-transferases (GSTs, Enzyme Commission 2.5.1.18) are a large family of cytosolic enzymes that catalyze the detoxification of reactive electrophilic compounds, including many environmental carcinogens (e.g., benzo[a]pyrene and other polycyclic aromatic hydrocarbons) [1,2]. Because individuals with the GSTM1 null genotype have been reported to have higher levels of polycyclic aromatic hydrocarbon-dGMP adducts (which can induce genetic mutations) in lung tissue than those with the GSTM1 genotype [4], such genetic variants have been extensively studied as candidates for lung cancer susceptibility, but studies have yielded apparently conflicting results [6–142]. This may be due, in part, to involvement of only a few hundred cases and a few hundred controls in most studies, too few to assess reliably any moderate genetic effects in lung cancer. They have done a lot of studies, some small, some large, to test whether there are associations between particular glutathione s-transferase gene variants and the risk of lung cancer

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