Genetic polymorphisms of microsomal epoxide hydroxylase and glutathione S-transferases M1, T1 and P1, interactions with smoking, and risk for esophageal (Barrett) adenocarcinoma

Background: The aim of this case-control study was to test the hypothesis that polymorphisms of the microsomal epoxide hydroxylase (mEH) and glutathione S-transferase (GST) genes modulate the susceptibility to esophageal adenocarcinoma (EADC) associated with smoking. Methods: Cases included patients with gastroesophageal reflux disease (GERD) (n = 126), Barrett esophagus (BE) (n = 125), and EADC (n = 56); controls comprised 95 strictly asymptomatic individuals. Genomic DNA was extracted from blood samples, and PCR-based assays were used to genotype mEH (slow allele, fast allele, predicted activity) and GSTM1, GSTT1 and GSTP1. Logistic regression was used to study associations between smoking and genotype, adjusting for age, gender and alcohol consumption. Results: Relative to asymptomatic controls, no significant differences were found for the distribution of mEH and GST polymorphic variants in cases with GERD, BE or EADC. Smoking was a risk factor for EADC, especially when cigarette exposure was greater than 30 pack-years (adjusted odds ratio [OR] 6.11, 95% confidence interval [CI] 2.2–17.32; P = 0.001). The strong association between smoking and EADC was seen preferentially in patients with the active allele of either GSTM1 (OR 7.9, 95% CI 1.14–54.76; P = 0.003) or GSTT1 (OR 3.2, 95% CI 1.23–8.35; P = 0.004). Conclusions: Cigarette smoking is an independent risk factor for EADC, and in particular for heavy smokers. The strong statistical association between smoking and risk for EADC in individuals with the active allele of either GSTM1 or GSTT1 may have potential clinical application in endoscopic surveillance programs to identify individuals with BE at increased risk for progression to EADC.