Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: A case-control analysis

Although tobacco is the major lung cancer risk factor, folate deficiency has also been implicated as a risk. Methionine synthase (MS; gene symbol, MTR) and methionine synthase reductase (MSR; gene symbol, MTRR) play important roles in the folate metabolism pathway. It was hypothesized that polymorphisms of MTR and MTRR are associated with lung cancer risk and interact with dietary intake of folate-related nutrients in lung cancer etiology. In a hospital-based, case-control study of 1035 lung cancer cases and 1148 controls of non-Hispanic whites, frequency matched by age, sex, ethnicity and smoking status, the MTR 2756A > G and MTRR 66A > G polymorphisms were genotyped. It was found that the MTRR G allele was associated with a significantly increased lung cancer risk [adjusted odd ratio (OR) = 1.34, 95% confidence interval (CI) = 1.06-1.70 for the AG genotype and OR = 1.39, 95% CI = 1.08-1.78 for the GG genotype compared to the AA genotype]. Further analysis suggested some evidence of gene-diet interactions between the MTRR 66A > G polymorphism and dietary intake of total folate and vitamin B₁₂. When the two polymorphisms were evaluated together by the number of the variant alleles (i.e. the MTR 2756G and MTRR 66A), lung cancer risk was significantly increased in a dose-dependent manner (P_trend = 0.045). The risk of lung cancer was 1.29 (0.98-1.69) for one variant allele, and 1.36 (1.04-1.77) for two or more variant alleles compared to the wild-type (0 variant allele) genotype. In conclusion, our data provide evidence supporting the association between the MTR 2756A > G and MTRR 66A > G polymorphisms and lung cancer risk, which may be modulated by dietary nutrient intake.