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

Abstract

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, I² = 41.9%); (CC vs. CA + AA: OR = 0.82, 95% CI: 0.52-1.30, P = 0.04, I² = 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.

Keywords: MTHFR; Male infertility; Polymorphisms.

Fig. 1

PRISMA flow chart for selecting relevant articles of MTHFR 677C/T

Fig. 2

Forest plot of male infertility risk associated with MTHFR 677C > T polymorphism [a for TT vs. CC; b for TC vs. CC; c for TT + TC vs. CC; d for TT vs. TC + CC]. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI

Fig. 3

Forest plot of male infertility risk associated with MTHFR 1298A/C polymorphism [a for CC vs. AA; b for CA vs. AA; c for CC + CA vs. AA; d for CC vs. CA + AA]. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI

Fig. 4

Funnel plot for publication bias test [for 677C > T polymorphism: a for TC vs. CC, p = 0.281; b for TT + TC vs. CC, p = 0.196; for 1298A > C polymorphism: c for CC vs. AA, p = 0.403; d for CC vs. CA + AA, p = 0.235]. Each point represents a separate study for the indicated association. Log [or], natural logarithm of OR. Horizontal line, mean effect size