title: Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury).
abstract: The human T developmental gene has been implicated in the etiology of neural tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We have investigated the frequency of the T allelic variant TIVS7-2 in 218 Irish NTD case-parent triads. This population showed the same trend as previously reported, with an excess of the TIVS7-2 allele among cases. Log-linear modeling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mothers (RR = 0.91). The TIVS7-2 allele is markedly associated with cases born before 1980 (RR = 2.09; CI = 1.23-3.55; corrected p = 0.030), but not with more recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show any increased tendency to be homozygous for the thermolabile variant of the folate-dependent enzyme 5,10-methylene tetrahydrofolate reductase, which is an established genetic risk factor for NTDs. Since the incidence of NTDs has declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk factor(s), the impact of which have been diminishing over time.
authors.affiliation: Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
authors.forename: D C
authors.initials: DC
authors.lastname: Shields
authors.forename: D
authors.initials: D
authors.lastname: Ramsbottom
authors.forename: C
authors.initials: C
authors.lastname: Donoghue
authors.forename: E
authors.initials: E
authors.lastname: Pinjon
authors.forename: P N
authors.initials: PN
authors.lastname: Kirke
authors.forename: A M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Y H
authors.initials: YH
authors.lastname: Edwards
authors.forename: J L
authors.initials: JL
authors.lastname: Mills
authors.forename: L
authors.initials: L
authors.lastname: Mynett-Johnson
authors.forename: D G
authors.initials: DG
authors.lastname: Weir
authors.forename: J M
authors.initials: JM
authors.lastname: Scott
authors.forename: A S
authors.initials: AS
authors.lastname: Whitehead
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D005326:Fetal Proteins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D051379:Mice; D009436:Neural Tube Defects / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D012306:Risk; D020825:T-Box Domain Proteins / Q000235:genetics*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein