Abstract
To investigate the association between the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) polymorphism rs 2236225 (c.1958G>A) and susceptibility to non-syndromic cleft of the lip and/or palate (NSCL/P). An extensive literature review has been conducted using PubMed, Web of Science, Cochrane Library, Google Scholar, the China National Knowledge Infrastructure (CNKI), and Wanfang Database for eligible researches. The terms for searching were "cleft lip OR cleft palate OR CLP OR CL/P OR oral facial cleft OR OFC" AND "methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 OR methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthetase OR MTHFD1 OR MTHFD". Two independent researchers screened, evaluated and extracted the data of included studies. The pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated by random effects model under five gene models. Subgroup, sensitivity analysis and publication bias were also assessed. Ten case-control studies have been included in the systematic review and eight studies have been considered for the meta-analysis. Overall, the MTHFD1 polymorphism rs2236225 and the risk of NSCL/P showed pooled OR (95% CI) of 1.02 (0.86-1.21) under allelic model. A higher degree of heterogeneity was observed in Asian countries (I (2) = 75.6%) compared to non-Asian countries (I (2) = 48.9%). Similar consequence appeared in the subgroup of children (I (2) = 78.6%) compared with that of mothers (I (2) = 0.0%). There was no significant difference in the publication bias by the Begg's funnel plot (P = 0.711) and Egger's regression test (P = 0.746). Our assessment suggested there was no significant association between the MTHFD1 polymorphism rs 2236225 (c.1958G>A) and the susceptibility to NSCL/P. Further investigations using a large sample size and a more advanced technique should be adopted to reach a more precise conclusion in the future.
Highlights
Cleft of the lip and/or palate (CL/P) is one of the most common facial malformations[1,2,3] and a societal burden, affecting the patient ability to eat and speak and influencing social integration[4]
Recent studies suggested that using folic acid could reduce the rates of oral clefts[6,7] and single nucleotide polymorphisms of some genes such as MTHFR8,9, MTR40 and MTRR involved in the metabolism of folic acid have been associated to high risk of NSCL/P8,9
Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a key gene associated with three sequential enzymatic reactions in the metabolism of folic acid, might play a potential role in the risk of non-syndromic cleft of the lip and/or palate (NSCL/P), especially the polymorphism rs2236225 (c.1958G>A)[10]
Summary
Cleft of the lip and/or palate (CL/P) is one of the most common facial malformations[1,2,3] and a societal burden, affecting the patient ability to eat and speak and influencing social integration[4]. Recent studies suggested that using folic acid could reduce the rates of oral clefts[6,7] and single nucleotide polymorphisms of some genes such as MTHFR8,9, MTR40 and MTRR involved in the metabolism of folic acid have been associated to high risk of NSCL/P8,9. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a key gene associated with three sequential enzymatic reactions in the metabolism of folic acid, might play a potential role in the risk of NSCL/P, especially the polymorphism rs2236225 (c.1958G>A)[10]. Different observations that linked the polymorphism rs2236225 to the risk of NSCL/P have been reported[11,12]. The suggestion of a link between rs2236225 polymorphism and susceptibility to NSCL/P might be result of the limitations in sample size, different ethnic populations and other environmental factors.
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