association between maternal mthfr polymorphisms and nonsyndromic cleft lip with or without cleft palate in offspring, a meta-analysis based on 15 case-control studies

background: the methylenetetrahydrofolate reductase (mthfr) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (nscl/p). however, conflicting results have been obtained when evaluating the association between maternal mthfr c677t and a1298c polymorphisms and the risk of nscl/p. in light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. materials and methods: a total of 15 case-control studies were ultimately identified after a comprehensive literature search and hardy-weinberg equilibrium (hwe) examination. cochrane’s q test and index of heterogeneity (i2) indicated no obvious heterogeneity among studies. results: fixed or random-effects models were used to calculate the pooled odds ratios (ors). the results showed that the tt genotype in mothers increased the likelihood of having nscl/p offspring 1.25 times (95% ci: 1.047-1.494) more than the cc homozygotes. meanwhile, maternal tt genotype increased the risk of producing nscl/p offspring in recessive model (or=1.325, 95% ci: 1.124-1.562). however, the ct heterozygote and the ct+tt dominant models had no association with nscl/p offspring compared with the cc wild-type homozygote model. subgroup analyses based on ethnicity indicated that maternal tt genotype increased the likelihood of having nscl/p offspring in whites (or=1.308, 95% ci: 1.059-1.617) and asians (or=1.726, 95% ci: 1.090-2.733) in recessive model. also, subgroup analyses based on source of control showed that mothers with the 677tt genotype had a significantly increased susceptibility of having nscl/p children in hospital based population (hb) when compared with cc homozygotes (or=1.248, 95% ci: 1.024-1.520) and under the recessive model (or=1.324, 95% ci: 1.104-1.588). furthermore, maternal a1298c polymorphism had no significant association with producing nscl/p offspring (dominant model or=0.952, 95% ci: 0.816-1.111, recessive model or=0.766, 95% ci: 0.567-1.036). conclusion: mthfr c677t polymorphism is associated with the risk of generating nscl/p offspring, and being a 677tt homozygote is a risk factor. mthfr a1298c polymorphism was not associated with generating nscl/p offspring. however, further work should be performed to confirm these findings.