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

ABSTRACT

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. 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 [I[2]] indicated no obvious heterogeneity among studies. 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]. 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: