title: 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: 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.
  
  
  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 (I(2)) 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 un- der 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China ; Medical College, Henan University of Science and Technology, Luoyang, China.
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Medical College, Henan University of Science and Technology, Luoyang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Yin
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Xiaozhuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Di
authors.initials: D
authors.lastname: Li
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Hongle
authors.initials: H
authors.lastname: Li
authors.affiliation: College of Public Health, Zhengzhou University, Zhengzhou, China.
authors.forename: Zengli
authors.initials: Z
authors.lastname: Yu
keywords: Cleft Lip; Meta-Analysis; Methylenetetrahydrofolate Reductase