This cross-sectional study investigated the gene-environment interactions between the MTHFR and MTR polymorphisms and gender with regard to lipid profiles in a general Chinese population. We recruited 2,124 individuals from Anhui Province, China. The MTHFR (C677T and A1298C) and MTR (A2756G) polymorphisms were genotyped, and serum lipid levels, including TC, TG, LDL-C, and HDL-C, were determined. Our results showed that male MTR AG + GG genotype carriers had significantly lower serum TC

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... d β ± [SE]:-0.25 ± 0.10 mmol/L; P = 0.0159), LDL-C (adjusted β ± [SE]:-0.24 ± 0.09 mmol/L; P = 0.0049), and HDL-C (adjusted β ± [SE]:-0.09 ± 0.03 mmol/L; P = 0.0055) levels than the AA carriers. Male MTHFR677TT genotype carriers had significantly higher serum TC (adjusted β±[SE]: 0.28 ± 0.13 mmol/L; P = 0.0287) and LDL-C (adjusted β ± [SE]: 0.26 ± 0.13 mmol/L; P = = 0.0378, 0.0054 and 0.0183 for interaction, respectively) . The interaction term for the MTHFR 677TT genotype and gender was also significant for TC and LDL-C levels (P = 0.0147 and 0.0243 for interaction, respectively). Further haplotype analysis showed that there also were significant interactions between gender and hap2 (MTHFR 677C/1298A) on TC (P = 0.009) and LDL-C (P = 0.013). We suggest that the negative effects of the MTR and MTHFR genotypes on serum lipids are based on certain gene-environment interactions in the Chinese general population. www.impactjournals.com/oncotarget 0.0485) levels than CC + CT carriers. In subsequent analyses, there was a significant interaction between the MTR AG+GG genotypes and gender in association with TC, LDL-C and TG levels (P