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Meta-Analysis
. 2025 Aug;37(8):e70119.
doi: 10.1002/ajhb.70119.

The Fertility Effects of the C677T Mutation in the Methylenetetrahydrofolate Reductase Gene: A Cross-Site Systematic Review and Meta-Analysis

Caroline A MacLean  1 , Miguel Dimanlig  2 , David Godfrey  1 , Lorena Madrigal  1
Affiliations
Meta-Analysis

The Fertility Effects of the C677T Mutation in the Methylenetetrahydrofolate Reductase Gene: A Cross-Site Systematic Review and Meta-Analysis

Caroline A MacLean et al. Am J Hum Biol. 2025 Aug.

Abstract

Introduction: In this research, we seek to understand the evolutionary forces which have resulted in the distribution of the MTHFR C677T single nucleotide polymorphism, which is associated with fertility-related, cardiovascular, cancerous, and neurological morbidities. Due to the negative effects of the gene, it is likely frequent due to genetic drift or natural selection.

Methods: Using secondary data gathered by systematic review, we test proposals stating that under conditions of ample folate, individuals who are heterozygous (CT) and homozygous (TT) for the MTHFR C677T polymorphism would suffer from fewer or no deleterious pregnancy or birth outcomes. Using descriptive and bivariate statistics, we determined if significant differences exist between pregnancy or birth outcomes based on genotype. We then modeled the effects of genotype, folate, cobalamin, and homocysteine (and their interactions) on the frequency of the pregnancy outcomes.

Results: Even with ample and high serum folate, CT and TT women sampled had worse pregnancy outcomes. Folate (sometimes interacting with insolation) mediates pregnancy outcomes in a genotype-dependent fashion. For this reason, we caution against the use of a "one size fits all" approach to clinical treatment for CT and TT individuals.

Conclusions: We conclude that natural selection is the primary force of evolution acting on this mutation despite its numerous negative effects. We reject the hypothesis that in conditions of ample folate supply, CT or TT pregnant people might have a fitness advantage. Genotype was a strong predictor of birth outcomes, indicating that for this polymorphism, there is a strong folate-genotypic and genotype-insolation interaction.

Keywords: MTHFR C677T; fertility; natural selection.

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References

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