Association between methylenetetrahydrofolate reductase polymorphisms and non-syndromic cleft lip with or without palate susceptibility: an updated systematic review and meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are thought to be involved in the development of cleft lip with or without cleft palate (NSCL/P), but published results are contradictory. We therefore designed an updated meta-analysis to pool eligible studies and to evaluate further the possible relations between MTHFR polymorphisms (c.677C>T and c.1298A>C) and susceptibility to NSCL/P. A comprehensive search based on PubMed, Medline, Web of Science, and Embase databases was made up to February 2018. Twenty-three case-control and 10 case-parent trio studies (including 1149 cases and 1161 controls) were retrieved. Odds ratio (OR) with 95% CI were used to estimate the pooled strength of association under different genetic models. The Q test and I² test were used to estimate heterogeneity among studies, the quality of which was assessed using the Newcastle-Ottawa scale. In the MTHFR c.677C>T polymorphism group, there were significant overall results for the recessive (OR 1.231, 95%CI 1.092 to 1.387) and homozygote (OR 1.252, 95%CI 1.078 to 1.456) models. Subgroup analysis by subjects and ethnicity identified only associations in European mothers for the recessive model and the homozygote model. For the c.1298A>C group, there were no significant results for either European or Asian patients for all genetic models. The MTHFR c.677C>T polymorphism might increase susceptibility to NSCL/P in European mothers, but was negatively associated in Asian patients, and the MTHFR c.1298A>C polymorphism is not involved in the development of NSCL/P in either European or Asian patients.