The relevance of MTHFR C677T, A1298C, and MTRR A66G polymorphisms with response to male infertility in Asians

Abstract

Although published studies have reported the association between MTHFR C677T (rs 1801133), A1298C (rs 1801131), and MTRR A66G (rs1801394) polymorphisms and male infertility in Asian populations, the results are conflicting. In order to accurately evaluate the relevance, a meta-analysis was performed. We searched for potential studies in 4 databases, containing PubMed, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang database until May 31, 2018. The summarized odds ratio (OR) with 95% confidence intervals (95% CI) were calculated to evaluate the relevance in 5 genetic models. The heterogeneity test, sensitivity analysis, and publication bias test was performed by Review Manager 5.3 software. Overall, 22 case–control studies with 5049 cases and 4157 controls were included in this meta-analysis, which contained 20 studies of MTHFR C677T polymorphism, 12 studies of MTHFR A1298C polymorphism and 4 studies of MTRR A66G polymorphism. The results indicated that MTHFR C677T, A1298C, and MTRR A66G polymorphisms were significantly associated with male infertility in Asian populations (Dominant model: MTHFR CC + CT vs TT: OR = 0.60, 95% CI (0.53, 0.67), P <.00001; MTHFR AA + AC vs CC: OR = 0.62, 95% CI (0.49, 0.79), P = .0001; MTRR AA + AG vs GG: OR = 0.60, 95% CI (0.45, 0.81), P = .001. Recessive model: MTHFR CC vs CT + TT: OR = 0.67, 95% CI (0.61, 0.74), P <.00001; MTHFR AA vs AC + CC: OR = 0.79, 95% CI (0.70, 0.88), P <.0001; MTRR AA vs AG + GG: OR = 0.70, 95% CI (0.56, 0.88), P = .002. Heterozygote model: MTHFR CC vs CT: OR = 0.74, 95% CI (0.67, 0.82), P <.00001; MTHFR AA vs AC: OR = 0.83, 95% CI (0.73, 0.93), P = .002; MTRR AA vs AG: OR = 0.76, 95% CI (0.60, 0.92), P = .02. Homozygote model: MTHFR CC vs TT: OR = 0.48, 95% CI (0.41, 0.56), P <.00001; MTHFR AA vs CC: OR = 0.61, 95% CI (0.39, 0.93), P = .02; MTRR AA vs GG: OR = 0.51, 95% CI (0.36, 0.72), P = .0001. Allele model: MTHFR C vs T: OR = 0.70, 95% CI (0.66, 0.75), P <.00001; MTHFR A vsC: OR = 0.82, 95% CI (0.71, 0.95), P = .01; MTRR A vs G: OR = 0.76, 95% CI (0.66, 0.88), P = .00003). Stratified analyses by geographical location and source of controls showed the same results. Sensitivity analyses indicated that the final consequences of this meta-analysis were stable, and the publication biases test had not found obvious asymmetry. This meta-analysis indicates that MTHFR C677T, A1298C, and MTRR A66G polymorphisms are the risk factors with susceptibility to male infertility in Asians.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and male infertility risk

“…Ullah et al [ 32 ] indicated that the MTHFR C677T polymorphism was associated with an increased risk of male infertility in Caucasians for middle income countries. Rai et al [ 22 ] and Shi et al [ 27 ] supported an association between C677T polymorphism and male infertility in Asians. Ren et al [ 25 ] suggested that the MTHFR C667T polymorphism may contribute to the genetic susceptibility to male infertility in the Chinese population.…”

“…In addition, ten previous meta-analyses [ 15 , 16 , 18 , 20 , 24 – 27 , 30 , 32 ] have also been published on the MTHFR A1298C polymorphism with male infertility risk (as shown in Table 7 ). Among these publications, one study [ 32 ] investigated this issue in Caucasians, one study [ 27 ] in Asians, one study [ 25 ] in Chinese population, and seven studies [ 15 , 16 , 18 , 20 , 24 , 26 , 30 ] in overall populations. Ullah et al [ 32 ] indicated that the MTHFR A1298C polymorphism was associated with an increased risk of male infertility in Caucasians for low income countries.…”

“…Ullah et al [ 32 ] indicated that the MTHFR A1298C polymorphism was associated with an increased risk of male infertility in Caucasians for low income countries. Shi et al [ 27 ] supported that MTHFR A1298C polymorphism was the risk factor with susceptibility to male infertility in Asians, especially in East Asians. Ren et al [ 25 ] demonstrated that MTHFR A1298C polymorphism may be unrelated to male infertility risk in Chinese population.…”

“…In addition, 15 previous meta-analyses [ 15 , 17 , 19 – 29 , 31 , 32 ] have been reported on the MTHFR C677T polymorphism with male infertility risk (as shown in Table 1 ). Among these publications, two studies [ 32 ] investigated this issue in Caucasians, two studies [ 22 , 27 ] in Asians, one study [ 25 ] in Chinese population, and 11 studies [ 15 , 17 , 19 – 21 , 23 , 24 , 26 , 28 , 29 , 31 ] in overall populations. Moreover, ten previous meta-analyses [ 15 , 16 , 18 , 20 , 24 – 27 , 30 , 32 ] have also been published on the MTHFR A1298C polymorphism with male infertility risk (as shown in Table 2 ).…”

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

“…Therefore, the Folate pathway is likely to be important in male fertility [ 6 ]. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism and plays a vital role in balancing the storage of methyl groups between DNA synthesis and its methylation [ 7 ]. DNA methylation is one of the important epigenetics features that play an essential role in regulating gene expression in spermatogenesis [ 8 ].…”