Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Thermolabile 5,10‐methylenetetrahydrofolate reductase (MTHFR) is the first folate‐related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD‐affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 μg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88–7.18; P < 0.001), and those with RCF less than 150 μg/L had eight times higher risk of NTD than subjects with levels over 400 μg/L. Plasma homocysteine levels of non‐TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD‐affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate‐dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food‐fortification program as a population strategy for reducing the occurrence of NTDs. Am. J. Med. Genet. 78:155–159, 1998. © 1998 Wiley‐Liss, Inc.