The 19‐bp deletion polymorphism in intron‐1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population

Periconceptional maternal folic acid supplementation can prevent up to 70% of pregnancies affected with neural tube defects (NTDs), including spina bifida. This has focused attention on folate-related genes such as dihydrofolate reductase (DHFR) in a bid to identify the genetic factors that influence NTD risk through either the fetal or maternal genotype. We considered a novel intronic 19-bp deletion polymorphism and two polymorphisms within the 3' untranslated region (721A>T and 829C>T) of the DHFR gene as candidates for NTD risk. We studied NTD cases (n=283), mothers of cases (n=280), fathers of cases (n=279), and controls (n=256). We did not find the DHFR 829C>T polymorphism to be variable within the Irish population. The 19-bp intron deletion and the 721A>T polymorphisms were found to be in linkage disequilibrium. In contrast to a previous study, the 19-bp intron deletion allele did show a significant protective effect in mothers of NTD cases when present in one (relative risk 0.59 [95%CI: 0.39-0.89], P=0.01) or two copies (relative risk 0.52 [95%CI: 0.32-0.86], P=0.01). Analysis of mRNA levels revealed a small increase in expression ( approximately 1.5-fold) associated with the 19-bp intron deletion polymorphism, but this was not significant. In conclusion, the DHFR intron 19-bp deletion allele may be a protective NTD genetic factor by increasing DHFR mRNA levels in pregnant women.