Genetic selection? A study of individual variation in the enzymes of folate metabolism

Barbara A Jennings,Jane Skinner,Gavin A Willis,Caroline L Relton

doi:10.1186/1471-2350-11-18

Abstract

BackgroundGenetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity.MethodsWe have looked at the prevalence of genetic variants of the enzymes MTHFR and TYMS in 2,898 DNA samples derived from five cohorts collected in the United Kingdom. The simultaneous analysis of genetic variants of the MTHFR and TYMS loci was carried out to investigate a putative gene-gene interaction that was first observed in an elderly male population from Norfolk.ResultsWe have made a consistent observation in five population cohorts; the proportion of individuals who are homozygous for the 2R allele of the 5'UTR TYMS polymorphism is less in individuals who are homozygous for the T allele of MTHFR 677 than in individuals homozygous for the C allele of MTHFR 677 (p = 0.02).ConclusionsThese data may suggest a gene-gene interaction and could be evidence of genetic selection, with some pregnancies more or less viable as a consequence of genetic variation. If these genetic phenomena affect the way folate is handled at the cellular level in utero it is possible that maternal folic acid intake may over-ride such genetic selection.

Highlights

Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity
SNPs and other polymorphisms of the genes MTHFR, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and thymidylate synthetase (TYMS) have been associated with cardiovascular disease, neural tube defects, Down syndrome and leukaemia [1,2,3,4]
Because of observations made in cross-sectional population studies to explore the impact of genetic variants of the enzymes MTHFR and TYMS on survival in elderly cohorts, we have studied the prevalence of two polymorphisms in younger populations

Summary

Introduction

Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity. Its efficient metabolism have well-established roles in disease prevention; deficiency is associated with increased risk of neural tube defects, vascular disease, cancer and anaemia [5]. Embryo development and viability has been the subject of many epidemiological studies of genetic variants, including, and possibly predominantly, in those genes involved in folate metabolism [2,3,4,7]. Women who are homozygous for a variant of the gene MTHFR (1298A>C) were less likely to produce a livebirth than other women undergoing IVF and the chances of a twin birth increased with plasma and red cell folate concentrations [8]. The authors proposed that the woman’s genotype is linked to her potential to produce good quality embryos and that this, coupled with folate status, increases the likelihood of IVF resulting in live births. Haggarty et al observed an association between raised concentrations of homocysteine and an increase in the risk of miscarriage in their study of women undergoing IVF and elevated homocysteine levels has been linked recurrent pregnancy loss previously [10]

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