Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury)

The human T developmental gene has been implicated in the etiology of neura l tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We hav e 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 mod eling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mother s (RR = 0,91), The TIVS7-2 allele is markedly associated with cases born be fore 1980 (RR = 2.09; CI = 1.23-3.55; corrected p = 0.030), but not with mo re recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show a ny 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 h as declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk f actor(s), the impact of which have been diminishing over time. Am. J, Med, Genet. 92:206-211, 2000, (C) 2000 Wiley-Liss, Inc.