Abstract
Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility.
Highlights
The MTHFR gene is located on chromosome 1 (1p36.3), and its protein product catalyzes the reduction of methylenetetrahydrofolate (5,10-methyl THF) to methyltetrahydrofolate (5-methyl THF), which donates a methyl group[10,11]
With regard to the MTHFR C677T mutation, Gupta N et al.[14] performed a meta-analysis which included 13 articles and concluded that MTHFR C677T was strongly associated with male infertility; the conclusions were inconsistent with the results from a more recent meta-analysis conducted by Weiner As et al in 2014 that analyzed the same number of studies[15]
The distribution of genotypes in all of the controls was consistent with Hardy-Weinberg equilibrium (HWE), except for nine case-control studies
Summary
The MTHFR gene is located on chromosome 1 (1p36.3), and its protein product catalyzes the reduction of methylenetetrahydrofolate (5,10-methyl THF) to methyltetrahydrofolate (5-methyl THF), which donates a methyl group[10,11]. With regard to the MTHFR C677T mutation, Gupta N et al.[14] performed a meta-analysis which included 13 articles and concluded that MTHFR C677T was strongly associated with male infertility; the conclusions were inconsistent with the results from a more recent meta-analysis conducted by Weiner As et al in 2014 that analyzed the same number of studies[15]. A single study, for studies with relatively small sample size, might be underpowered to reveal a small effect of the polymorphisms on disease risk[21] To address this issue, we performed a meta-analysis with subgroup analyses from all eligible studies to obtain a more precise estimation of the relationships between mutations in folate-related enzyme genes and male infertility. We analyzed the MTHFR haplotype and conducted trial sequential analysis
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