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This study aimed to examine the joint effects of folate intake, polymorphisms of 5,10- methylenetetrahydrofolate reductase ( MTHFR),  methionine synthesis reductase ( MTRR ) and methionine synthase ( MTR ) genes and breast cancer risk. A case-control study of 570 consecutively recruited breast cancer cases and 576 controls was conducted in Guangzhou, China. Multifactor dimensionality reduction and logistic regression approach were used to evaluate gene-gene interaction. The covariates were chosen based on comparison of baseline characteristics of cases and controls. Folate intake was found to be inversely associated with breast cancer risk. The  MTRR rs162036 GG genotype was associated with a decreased risk of breast cancer [adjusted odds ratio (OR) 0.41, 95% confidence interval (CI) 0.20–0.85]. Compared with the wild-type group ( MTRR rs162036 AA with  MTR rs1805087 AA)  MTRR rs162036 AA with  MTR rs1805087 GA + GG was associated with a decreased risk (OR 0.70, 95% CI 0.48–1.03). With the combined  MTHFR rs1801131 TT and  MTHFR rs1801133 GG genotypes as a reference,  MTHFR rs1801131 TT with  MTHFR rs1801133 GA + AA was associated with a decreased risk (OR 0.78, 95% CI 0.57 – 1.08) and  MTHFR rs1801131 GT + GG with  MTHFR rs1801133 GA + AA was associated with an increased risk (OR 1.35, 95% CI 0.88–2.05). The joint impact of  MTRR rs162036 and  MTR rs1805087,  MTHFR rs1801131 and  MTHFR rs1801133, folate and  MTHFR rs1801133 may contribute to breast cancer risk.

Joint effects of folate intake and one-carbon-metabolizing genetic polymorphisms on breast cancer risk: a case-control study in China