title: 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.
abstract: 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.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. anne.parle-mcdermott@dcu.ie
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Gibney
authors.forename: James
authors.initials: J
authors.lastname: Troendle
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Leary
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Mary
authors.initials: M
authors.lastname: Conley
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D020029:Base Pairing; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics*; D007494:Ireland; D008297:Male; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D017384:Sequence Deletion / Q000235:genetics; D016135:Spinal Dysraphism / Q000201:enzymology* / Q000235:genetics*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D013762:Tetrahydrofolate Dehydrogenase