Role of Xenobiotic-Metabolizing Enzyme Gene Polymorphisms and Interactions with Environmental Factors in Susceptibility
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Role of Xenobiotic-Metabolizing Enzyme Gene Polymorphisms and Interactions with Environmental Factors in Susceptibility to Gastric Cancer in Kashmir Valley Manzoor A. Malik & Rohit Upadhyay & Rama D. Mittal & Showket A. Zargar & Dinesh R. Modi & Balraj Mittal
Published online: 12 June 2009 # Humana Press Inc. 2009
Abstract Background Kashmir Valley has elevated incidence rate of gastric cancer (GC) and several environmental, host genetic factors have been suspected for it. Xenobiotic carcinogen exposure and interindividual differences in its cellular metabolism may modulate susceptibility to GC. Aim of the Study The aim of this study is to investigate the role of genetic variants of xenobiotic-metabolizing genes with susceptibility to GC in Kashmir Valley. Methods A case–control study was performed in 303 subjects (108 GC and 195 healthy controls) to analyze the association of polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3, CYP1A1, and CYP2E1 genes in susceptibility to GC in Kashmir Valley. All subjects were genotyped through polymerase chain reaction–restriction fragment length polymorphism. Results GSTM1null and CYP2E1c1c2 genotypes imparted risk for GC (odds ratio [OR]=1.98, 95% confidence interval [95%CI]=1.22–3.21, P=0.006 and OR=2.56, 95%CI= 1.25–5.25, P=0.010, respectively). GSTM3AB genotype/B allele was found to be associated with low risk for GC. Smokers and high salted tea consumers themselves were at M. A. Malik : R. Upadhyay : R. D. Mittal : B. Mittal (*) Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow 226014, India e-mail: [email protected] S. A. Zargar Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir 190011, India D. R. Modi Department of Biotechnology, Babasaheb Bhimrao Amabedkar University, Lucknow 226025, India
higher risk for GC (OR=8.98, 95%CI=5.16–15.62, P= 0.0001 and OR=14.78, 95%CI=8.02–27.23, P=0.0001, respectively). Cancer risk was further enhanced in smokers with the GSTM1null genotype. Conclusion The results suggest that GSTM1null, GSTM3AB, and CYP2E1c1c2 genotypes modulate the risk of GC whereas GSTM1null genotypes enhance the risk of GC for smokers in the Kashmir population. Keywords cancer susceptibility . gastric cancer . gene–environment interactions . xenobiotic-metabolizing enzymes
Introduction Gastric cancer (GC) represents the second most frequent cancer in the world in which nutritional, infectious, and genetic factors have been shown to play a role in its complex, multifactorial, and multistage process [1]. Interindividual differences in the cellular mechanisms of the activation and detoxification of carcinogenic chemicals may confer different degrees of susceptibility to cancer [2]. Several enzymes are involved in the detoxification of xenobiotic compounds. Cytochrome P450 (CYPs) are phase I enzymes responsible for activating most environmental precarcinogens, whereas glutathione S-transferases (GSTs) are phase II enzymes capable of detoxifying the electrophile car
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