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Background and objectives  One of the possible male sterility risk factors are polymorphisms of Methylenetetrahydrofolate reductase ( MTHFR ). However, the epidemiologic investigations described inconsistent results regarding  MTHFR  polymorphism and the risk of male infertility. For that reason, we carried out a meta-analysis of published case-control studies to re-examine the controversy.    Methods  Electronic searches of Cochrane, EMBASE, Google Scholar, and PubMed were conducted to select eligible studies for this meta-analysis (updated to May 2019). According to our exclusion and inclusion criteria, only high-quality studies that remarked the association between  MTHFR  polymorphisms and male infertility risk were included. The Crude odds ratio (OR) with a confidence interval of 95% (CI) was used to assess the relationship between MTHFR polymorphism and male infertility risk.    Results  Thirty-four case-control studies with 9662 cases and 9154 controls concerning 677C/T polymorphism and 22 case-control studies with 5893 cases and 6303 controls concerning 1298A/C polymorphism were recruited. Both  MTHFR  polymorphisms had significant associations with male infertility risk (CT + TT vs. CC: OR = 1.37, 95% CI: 1.21–1.55,  P  = 0.00, I 2  = 41.9%); (CC vs. CA + AA: OR = 0.82, 95% CI: 0.52–1.30,  P  = 0.04, I 2  = 50.1%). Further, when stratified by ethnicity, the significant association results were observed in Asians and Caucasians for 677C/T and just Asians for 1298A/C.    Conclusions  Some of  MTHFR  polymorphisms like MTHFR 677C > T are associated with an elevated male infertility risk. To confirm our conclusion and to provide more accurate and complete gene-environment communication with male infertility risk, more analytical studies are needed.

Association of the MTHFR 677C>T and 1298A>C polymorphisms and male infertility risk: a meta-analysis