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Editor—The mechanisms underlying the reduction in risk for neural tube defect (NTD) affected pregnancies by maternal folic acid supplementation are unknown. Current research efforts are focusing on candidate genes that encode enzymes involved in folate metabolism. Since homocysteine levels have been raised in some women who delivered infants with NTDs,1 2 the enzymes involved in both folate and homocysteine metabolism have received particular attention. Some, but not all, epidemiological data suggest an association between the C677T mutation in methylenetetrahydrofolate reductase (MTHFR) and increased risk for NTDs.3-6 No association between mutations in cystathionine β synthase and NTD risk has been observed.7 The epidemiological data pertaining to genetic variants of methionine synthase are quite limited.8 9 Methionine synthase catalyses the methylation of homocysteine to methionine using 5-methyltetrahydrofolate, the product of the MTHFR reaction, as the carbon donor. Thus, the investigation of genetic variants of methionine synthase is a prudent area of enquiry for exploring the mechanism underlying the reduction in NTD risk associated with maternal folic acid intake.
A polymorphism in methionine synthase was recently identified and shown to have an allele frequency of 15%.10 11 This mutation converts the acidic residue, aspartate, to an uncharged amino acid, glycine, and could conceivably affect enzyme activity. We therefore investigated the potential association between this genetic variant and NTD risk in infants.
Using data from two California population based case-control interview studies12 13 (1987-1991 birth cohorts), we investigated whether the variant alleles of the methionine synthase gene were more frequent among NTD case infants than control infants. The current analyses were restricted to: (1) liveborn infants diagnosed with spina bifida whose mothers completed an interview and whose DNA was available from stored newborn screening blood specimens (246 of 425 eligible), and (2) control infants without congenital anomalies, selected randomly from all infants born alive in the same geographical area and time period as the cases, whose mothers completed an interview and whose DNA was available (910 of 1296 eligible). To reduce potential effect modification associated with maternal vitamin supplementation, the 246 cases and 910 controls were further restricted to those women who did not use multivitamins containing folic acid in the periconceptional period (one month before to three months after conception). The data were also restricted to those women whose ethnicity was either non-Hispanic white or Hispanic white. A total of 95 case and 160 control infants comprised the analytical study base.
DNA was extracted from dried blood on newborn screening filter papers by standard laboratory procedures and was amplified by PCR using published primer sequences.10 Genotyping for the methionine synthase gene was performed by restriction digestion withHaeIII followed by gel electrophoresis.10 Cases and controls were genotyped GG if homozygous for the mutant allele, AG if heterozygous, and AA if homozygous for the wild type allele.
Case and control infants had similar overall percentages of GG (1 and 4%, respectively) and AG (32 and 31%, respectively) genotypes (table1). Percentages between cases and controls were also similar for each of the two ethnic groups studied. The odds ratios for spina bifida infants with either the GG or AG genotypes were not increased.
Our results do not indicate an increased risk for spina bifida among infants homozygous or heterozygous for the mutant genotype associated with methionine synthase. This study comprised the largest number of NTD cases so far examined for this methionine synthase variant. Two previously published studies8 9 of this variant and NTD risk did not observe an increased risk.
We purposely restricted our study population to infants whose mothers did not use multivitamins containing folic acid in the periconceptional period under the assumption that these infants would be the most likely to show an association with the variant genotype. Our study explored only infant genotype. Maternal genotype (heterozygotes and homozygotes) may also be important because it is possible that the recognised reduced risk for NTDs associated with maternal vitamin use is the result of a correction of a maternal metabolic defect, rather than that of the fetus. Nevertheless, given the infrequency of the GG genotype in the population (about 4% in these data), it is unlikely that the GG genotype (infant or mother) substantially contributes to a large proportion of folic acid preventable NTDs. Clearly, the mechanism underlying the NTD risk reduction by folic acid supplementation is an important question for understanding the aetiology of folic acid preventable birth defects. Continued investigation of genes encoding other folate related enzymes is needed.
The authors are grateful to Nelly Sabbaghian for technical assistance. This work was supported by the California Birth Defects Monitoring Program and the Medical Research Council of Canada.