A common variant in methionine synthase reductase combined with low cobalamin (vitamin B-12) increases risk for spina bifida

Impairment of folate and cobalamin (vitamin B-12) metabolism has been obser ved in families with neural tube defects (NTDs). Genetic variants of enzyme s in the homocysteine remethylation pathway might act as predisposing facto rs contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C --> T mutation in methylenetetrahydrofolate reductase (M THFR). We now report a polymorphism in methionine synthase reductase (MTRR) , the enzyme that activates cobalamin-dependent methionine synthase. This p olymorphorism, 66A --> G (I22M), has an allele frequency of 0.51 and increa ses NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients wi th spina bifida, 58 mothers of patients, 97 control children, and 89 mother s of controls. Cases and case mothers were almost twice as likely to posses s the homozygous mutant genotype when compared to controls, but this differ ence was not statistically significant. However, when combined with low lev els of cobalamin, the risk for mothers increased nearly five times (odds ra tio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homo zygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95 % CI 0.58-14.8), This study provides the first genetic link between vitamin B-12 deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted. (C) 1999 Academic Press.