Is MTHFD1 polymorphism rs 2236225 (c.1958G>A) associated with the susceptibility of NSCL/P? A systematic review and meta-analysis

Abstract

Aims: 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). Methods: 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. Results: 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). Conclusion: 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.

Association of a Polymorphism in the Gene Encoding Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) 1958G>A with Orofacial Cleft

“…With 170 samples, the control group was considerably larger, but not consistent with HWE-. In comparison, in the other Asian (Indian and Chinese) studies that indicated a significant association of the same polymorphism and orofacial cleft, the genotypes of the control group were consistent with HWE [6,12,19]. Therefore, it appears reasonable to suggest an extension of the present study to a larger case group, for example classified according to the type of cleft, and to extend the comparison to another control group, both from the same ethnic origin.…”

“…The possible effects of ethnic origin, as well as the type of oral cleft (lip, palate or both), may warrant further study [4]. The conclusions have been generally consistent for a number of the reviewed studies that have included all these types of nonsyndromic cleft cases, and a wide range of populations with different ethnic origins [19,20]. Nevertheless, the overall coverage may be instructive but by no means complete: for example, the coverage on African and South-East Asian populations remains rather poor.…”

“…In contrast to studies of Asian populations, most previous studies involving European (Norwegian, Italian, and Polish) and South American (Brazilian) populations indicated no significant association of this polymorphism with the risk of orofacial cleft [13][14][15][16][17], although one study also suggested such an association in a European (Irish) population [18]. More recently, a review including meta-analyses has casting doubts on the reported association when including studies on Asian populations [19]. Another study has confirmed the lacking association in a wider range of European populations from 11 countries [20].…”

Whole‐genome sequencing in a pair of monozygotic twins with discordant cleft lip and palate subtypes

“…In addition, previous reports suggested that TPM1 polymorphisms might also contribute to the etiology of NSCLP (Moreno Uribe et al., ; Qian et al., ). Further investigations in a large sample are needed to reach a more precise conclusion in the future (Zhao et al., ).…”

Methylenetetrahydrofolate reductase C677T polymorphism is not associated with the risk of nonsyndromic cleft lip/palate: An updated meta-analysis

“…Nutritional factors, such as the adequacy of folic acid in the mother's diet, are clearly important, but other potential disturbances in ovulation or development of fetus may be due to the activity of key factors such as the MTHFR enzyme in folate metabolism 10,11 . In addition, the role of other polymorphisms of folate metabolism has been proven in recent meta-analyses 7,12,13 . There are six published meta-analyses related to our topic in the literature 7,8,[14][15][16][17] .…”