Common dihydrofolate reductase 19–base pair deletion allele: a novel risk factor for preterm delivery1–3

Abstract

The DHFR 19-base pair deletion allele may be a risk factor for preterm delivery. In the presence of low dietary folate, the allele may also be a risk factor for low birth weight. This may be a gene-environment interaction.

Association between SNPs in genes involved in folate metabolism and preterm birth risk

“…When the intron 1 is present in the Chinese hamster ovary cells, DHFR is higher than that of intron deletion cells, and the protein encoded by the intronless construct is unstable because of lysosomal degradation. Therefore, the DHFR 19-bp deletion allele may be a risk factor for preterm delivery, which may depend on gene-environment interactions (Johnson et al, 2005). However, we found a weak correlation between the DHFR 19-bp deletion and preterm birth in the Chinese population.…”

“…The gene encoding DHFR is located on chromosome 5q14.1 and contains a common polymorphism in intron 1 of a 19-bp deletion, preventing the interaction between the specificity protein 1 transcription factor; intron 1 of many genes is typically a regulatory sequence Takayanagi et al, 1992;Guérin et al, 1995;Clark et al, 1997). Johnson et al (2005) studied 324 pregnant women in the impoverished area of Camden, NJ, in the US. Women with a DHFR gene deletion allele showed a significantly higher risk of preterm delivery (adjusted OR = 3.0) compared to women without a deletion allele.…”

“…Women with a DHFR gene deletion allele showed a significantly higher risk of preterm delivery (adjusted OR = 3.0) compared to women without a deletion allele. Women with both a DHFR deletion allele and low folate intake (<400 g/day from diet plus supplements) showed a significantly higher risk of preterm delivery and significantly higher risk of delivering an infant with a low birth weight compared to women without a deletion allele and with folate intake ≥400 g/day (Johnson et al, 2005). This polymorphism can reduce the transcription and transportation of folic acid to the fetus.…”

Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels

“…We did not observe this variant in the subjects that were included in the sequence analysis, suggesting that it is a population-specific polymorphism or has a minor allele frequency below 2.5%. Johnson et al 20,27 identified a 19-bp deletion in the highly conserved intron 1, which may be a maternal risk factor for having a child with spina bifida and preterm delivery. It has been postulated that this variant deletes a putative SP1 transcription factor-binding site (required for transcriptional activation/repression) or may affect the splicing process.…”

Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer

“…Determinants for some of this variation may be differing activity of TYMS [1Á3], TP [4Á7], and DHFR [8] deriving from germline genetic characteristics such as polymorph tandem repeat and single nucleotide polymorphism (SNP) in the promoter enhancer region of TYMS [9], and individual differences in TP protein expression [4], and short sequence deletions and SNP for DHFR [10].…”