Association of MTHFR 1298A > C Polymorphism with Susceptibility to Non-Syndromic Cleft Lip with or without Palate: A Case-Control Study and Meta-Analysis

Fetal Pediatr Pathol. 2021 Feb;40(1):1-17. doi: 10.1080/15513815.2019.1683918. Epub 2019 Nov 4.


Background: Several studies have evaluated association of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene 1298A > C polymorphism with non-syndromic cleft lip with or without palate (NSCL ± P) susceptibility, however the results are inconsistent.

Materials and methods: To address this issue, we performed a case-control study to evaluate the association of MTHFR 1298A > C polymorphism with NSCL ± P risk, followed by a meta-analysis.

Results: Including our study, a total of 22 case-control studies with 2,814 cases and 4,199 controls were selected. The results suggested that there was no significant association between MTHFR 1298A > C polymorphism and NSCL ± P risk overall. The subgroup analysis demonstrated that the polymorphism was significantly associated with NSCL ± P risk in Asians and Iranian populations, but not in Caucasians, mixed and Chinese populations.

Conclusion: This meta-analysis indicates that MTHFR 1298A > C polymorphism may not contribute to NSCL ± P risk in overall. However, the MTHFR 1298A > C polymorphism was significantly associated with an increased risk of NSCL ± P in Asians and Iranian populations.

Keywords: Cleft lip; MTHFR gene; cleft palate; meta-analysis; polymorphism.

Publication types

  • Meta-Analysis

MeSH terms

  • Case-Control Studies
  • Cleft Lip* / genetics
  • Cleft Palate* / genetics
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Iran
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Polymorphism, Single Nucleotide


  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)