The MTHFR 677C → T polymorphism and the risk of congenital heart defects: A literature review and meta-analysis

I. M. van Beynum, M. den Heijer, H. J. Blom, L. Kapusta

Research output: Contribution to journalReview articlepeer-review


Background: Periconceptional folic acid supplementation may protect against congenital heart defects (CHDs). Identification of candidate genes in folate metabolism has suggested that the 677C→T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be particularly associated with the risk of CHDs. Aim: To assess the relationship between MTHFR 677C→T and CHDs by literature review and meta-analysis. Methods: Studies were identified by searches of electronic literature for papers focussing on MTHFR 677C→T and the risk of any type of CHD. Both case-control comparisons and transmission-disequilibrium tests (TDTs) in family-based designs were included. Results: We found 13 eligible studies. Of 10 case-control studies, four focused on the fetal polymorphism, two studied the maternal polymorphism, and a further four investigated both. Three further publications used a family-based association study to assess the effect of the T allele on cardiac development. Overall analysis yielded odds ratios of 1.3 (95%CI 0.97 - 1.73) and 1.2 (95%CI 0.83 - 1.74) for fetal and maternal MTHFR TT genotypes, respectively. TDTs revealed no association between fetal 677T allele and CHDs. Discussion: This relatively small meta-analysis found no substantial evidence of increased CHD risk in individuals with MTHFR 677CT and TT genotypes. Heterogeneity regarding population background, study design and type of heart defects complicates the pooling and comparison of the studies. The effect of modification by periconceptional folic acid intake should be taken into account. Further larger studies and well-defined phenotypic subcategory analyses are needed to decide whether the MTHFR 677C→T polymorphism of the affected child and/or their mother is truly a risk factor for the development of CHDs.

Original languageEnglish
Pages (from-to)743-753
Number of pages11
JournalQJM - Monthly Journal of the Association of Physicians
Issue number12
StatePublished - Dec 2007
Externally publishedYes


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