Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women

Objective: This study aimed to investigate whether polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with age at menarche and age at natural menopause in white women. Methods: In a cross-sectional study, a total of 305 randomly selected unrelated white women were genotyped for six single nucleotide polymorphisms (SNPs) of the MTHFR gene (including one common replacement, rs1801133). This sample was comprehensively analyzed for the association of the SNPs with age at menarche. Then a subsample of 210 women who experienced natural menopause was analyzed for the association of the MTHFR gene with age at natural menopause. Results: Duration of breast-feeding was a significant predictor of earlier natural menopause (P <0.05). No individual SNPs were associated with either age at menarche or age at natural menopause. However, three significant (P <0.05) SNP-SNP interaction effects (rs2066470/rs1476413, rs2066470/rs4846049, and rs17037390/rs4846049) on the onset of menarche were determined. Three haplotypes were significantly associated with age at menopause (P <0.05). Four SNPs (rs2066470, rs17037390, rs1801133, and rs4846048) indicated significant interaction effects with various lifestyle factors on age at natural menopause. Conclusions: The results of our study suggest that the MTHFR gene may influence the onset of menarche and natural menopause. This effect is probably due to the multiple SNP-SNP and SNP-environment interactions. More independent studies are needed to further clarify the possible contribution of this gene to the timing of menarche and menopause.