The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk...

Area of Science:

• Genetics
• Maternal Health
• Developmental Biology

Background:

• Neural tube defects (NTDs) are significant birth defects, preventable by periconceptional folic acid. Genetic factors influencing NTD risk are under investigation.
• The dihydrofolate reductase (DHFR) gene is crucial in folate metabolism and has been implicated in NTD risk. Genetic variations in DHFR may affect susceptibility through maternal or fetal genotypes.

Purpose of the Study:

• To investigate the association between specific dihydrofolate reductase (DHFR) gene polymorphisms and the risk of neural tube defects (NTDs).
• To explore the potential role of maternal DHFR genotype in influencing NTD risk in offspring.

Main Methods:

• Genotyping was performed for three DHFR polymorphisms: an intronic 19-bp deletion and two 3' untranslated region polymorphisms (721A>T, 829C>T).
• The study included NTD cases, their mothers and fathers, and unrelated controls from the Irish population.
• Linkage disequilibrium and allele/genotype frequencies were analyzed to determine associations with NTD risk.

Main Results:

• The DHFR 829C>T polymorphism was not found to be polymorphic in the studied Irish population.
• The intronic 19-bp deletion and the 721A>T polymorphisms were in linkage disequilibrium.
• The DHFR 19-bp intron deletion allele demonstrated a significant protective effect in mothers of NTD cases, with reduced risk observed for one or two copies of the allele (RR 0.59-0.52).

Conclusions:

• The DHFR intron 19-bp deletion allele appears to be a protective genetic factor against NTDs in mothers.
• This protective effect may be mediated by a modest, though not statistically significant, increase in DHFR mRNA levels associated with the deletion allele.