Association of Xenobiotic Metabolizing Enzymes Genetic Polymorphisms With Esophageal Cancer in Kashmir Valley and Influence of Environmental Factors

Abstract

The Kashmir Valley has an elevated incidence rate of esophageal cancer (EC). Several environmental and genetic factors have been suspected for development of EC. A case-control study was performed in 135 EC patients and 195 healthy controls to analyze association of polymorphisms in glutathione S-transferase (GST) mu (GSTM1), GST theta (GSTT1), GST pi (GSTP1), GSTM3, Cytochrome P450 (CYP)1A1, and CYP2E1 genes with susceptibility to EC as well as their interaction with environmental factors such as smoking and high consumption of salted tea in Kashmir valley. All subjects were genotyped through polymerase chain reaction restriction fragment length polymorphism. Data was statistically analyzed using the chi-square test and logistic regression model. Results showed that GSTP1313 val/val and CYP2E1c1c2 genotypes imparted risk for esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma [EADC; odds ratio (OR) = 3.24, 95% confidence interval (CI) = 1.30–8.05; OR = 4.20, 95% CI = 1.65–10.70], respectively. GSTM3AB genotype/B allele was found to be associated with low risk for EC. Tobacco smoking through hukka (water pipe) and consumption of salted tea itself were high risk factors for developing EC (OR = 21.44, 95% CI = 11.63–39.54; OR = 14.86, 95% CI = 8.41–26.24), and the risks were modulated through the interaction of GSTM3AB, GSTP1val/val genotypes. In conclusion, GSTP1val/val and CYP2E1c1c2 genotypes/c2 allele increased the risk of ESCC and EADC, respectively, in the Kashmiri population; whereas GSTM3AB genotype imparted lower risk for both ESCC and EADC.

ACKNOWLEDGMENTS

The work was supported by a research grant from the Indian Council of Medical Research (ICMR), New Delhi. The authors thank Bashir Ahmad, Ghulam Mustafa, and faculty members of Gastroenterology Department, SKIMS, Srinagar for their help in sample collection. Manzoor Ahmad Malik and Rohit Upadhyay both contributed equally.

Notes

^a Abbreviations are as follows: EC, esophageal cancer; OR, odds ratio; CI, confidence interval. OR is age and gender adjusted. Significant values shown in bold.

^b n = 135.

^c n = 195.

^d Data missing.

^a Abbreviations are as follows: CYP, cytochrome P; GST, glutathione S-transferase; OR, odds ratio; CI, confidence interval; GSTM, GST mu; GSTT, GST tau; GSTP, GST pi; bp, base pair; ile, isoleucine; val, valine. OR is age and gender adjusted. Significant values shown in bold.

^b N = 195.

^c N = 135.

^a Abbreviations are as follows: ESCC, esophageal squamous cell carcinoma; OR, odds ratio; CI, confidence interval; EADC, esophageal adenocarcinoma; GSTP, glutathione S-transferase (GST) pi; ile, isoleucine; val, valine; GSTM, GST mu; bp, base pair; CYP, cytochrome P; NC, not calculated. OR is age and gender adjusted. Significant values shown in bold.

^a Abbreviations are as follows: EC, esophageal cancer; OR, odds ratio; CI, confidence interval; GSTM, glutathione S-transferase (GST) mu; GSTP, GST pi. OR is age and gender adjusted. Significant values shown in bold.

^b Data missing in some subjects.

^c N = 155.

^d N = 133.

^e N = 181.

^f N = 107.

^a Abbreviations are as follows: GSTM, glutathione S-transferase (GST) mu; GSTT, GST tau; GSTP, GST pi; CYP, cytochrome P.