Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR)C677T gene polymorphism in familial spina bifida

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SE. However, the mechanism is unknown, We tested a series of mul ticase SE families in which 224 individuals were genotyped and a group of 2 15 unrelated unaffected (external) control individuals for association of S E with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T po lymorphism that produces a heat-labile enzyme protein. The data were analyz ed using first the transmission/disequilibrium test (TDT) and second a modi fied case-control study design with Monte Carlo sampling methods. No associ ation of SE with the MTHFR T allele was found by either method. Presently, association between SE and the T allele has been found in four studies, a D utch study, an Irish study, a North American study, and an Italian study. B ut no association was found in four other studies, a British study, a Frenc h study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SE with this allele that was n ot significant at the P < 0.05 level. The present study finds no evidence o f the association. Only one other study, the German study, has used TDT ana lysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SE in some population s but not others, Major genetic risk factors for folate-related SE remain t o be found. Am. J. Med. Genet. 87:407-412, 1999 (C) 1999 Wiley-Liss, Inc.