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

ABSTRACT: Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity.We 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.We 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).These 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.

SUBMITTER: Jennings BA

PROVIDER: S-EPMC2835673 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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

Jennings Barbara A BA Willis Gavin A GA Skinner Jane J Relton Caroline L CL

BMC medical genetics 20100201

<h4>Background</h4>Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity.<h4>Methods</h4>We 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 ...[more]

PMID: 20122156

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Project description:Folic acid is critically important for normal neural development and has been implicated in pediatric brain tumor (PBT) risk. However, much work remains in understanding the genetic basis of these associations among at-risk populations. Therefore, we examined inherited variation in folate metabolism genes on PBT risk in individuals with Neurofibromatosis Type 1 (NF1), a cancer predisposition syndrome. We also evaluated maternal genetic variation in these genes that could serve as a proxy for the intrauterine nutrient environment that may be important in PBT development. We recruited 56 families with a child with NF1 and a PBT from the Washington University NF1 Patient Registry Initiative (NPRI) (https://nf1registry.wustl.edu/) or the St. Louis Children's Hospital Neurofibromatosis Clinical Program. DNA isolated from blood or buccal samples representing 45 triads (mother, father, child) and 11 dyads (mother, child) were analyzed using 49 tag single nucleotide polymorphisms (SNPs) genotyped on the Sequenom platform. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between maternal and offspring minor alleles and PBTs were estimated using log linear regression models. Significant/marginally significant associations between PBTs and each additional offspring copy of the minor allele were found for MTRR rs10520873 (OR = 0.5; 95% CI 0.3-1.0); MTR rs4659745 (OR = 0.5, 95% CI 0.2-0.9), rs3768147 (OR = 1.9; 1.1-3.3), rs12759827 (OR = 0.5, 95% CI 0.3-1.0); and DHFR rs10072026 (OR = 0.2; 95% CI 0.03-0.7). For maternal SNPs, significant/marginally significant associations were observed with each additional maternal copy of the minor allele for MTRR rs1802056 (OR = 1.94; 95% CI 1.1-3.6); SLC19A1 rs1051298 (OR = 2.0; 95% CI 1-3.4), rs2838957 (OR = 1.8; 1.0-3.4), rs4818789 (OR = 1.9; 95% CI 1.0-3.8), TYMS rs15872 (OR = 0.6; 95 %CI 0.3-1.0); and MTHFR rs3737964 (OR = 2.1; 95%CI 1.0-4.5) and rs1801133 (OR = 0.4; 95% CI 0.2-0.8). While our findings require validation, they suggest that inherited and maternal genetic variation in folate metabolic genes may influence PBT risk in children with NF1.

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

Publications

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

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