LOW BLOOD FOLATES IN NTD PREGNANCIES ARE ONLY PARTLY EXPLAINED BY THERMOLABILE 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE - LOW FOLATE STATUSALONE MAY BE THE CRITICAL FACTOR

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the f irst folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocystei ne levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relati onship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for th e TT genotype was associated with very low folate status among both th e cases (n = 13) and the controls (n = 21). However, after exclusion o f TT homozygotes, only 10% of the remaining 240 controls had RCF level s less than 200 mu g/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 R CF less than 150 mu g/L had eight times higher risk of NTD than subjec ts with levels over 400 mu g/L. Plasma homocysteine levels of non-TT c ases were also higher than those of controls (P = 0.047). This study s hows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a stra tegy of genetic screening of all childbearing women for this variant w ould be ineffective as a method of primary prevention of NTDs. The dat a suggest that low maternal folate status is itself the major determin ant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emph asize the importance of a food-fortification program as a population s trategy for reducing the occurrence of NTDs. Am. J. Med. Genet. 78:155 -159, 1998. (C) 1998 Wiley-Liss, Inc.