Neural tube defects (NTDs) are multifactorial in their etiology, having both genetic and environmental factors contributing to their development. Recent evidence demonstrates that periconceptional supplementation of the maternal diet with a multivitamin containing folic acid significantly reduces the occurrence and recurrence risk for having a pregnancy complicated by NTDs. Unfortunately, the mechanism underlying the beneficial effects of folic acid remains unknown. NTD surveillance data from the Texas-Mexico border show that the high NTD rate (28/10,000 live births) noted during the 1990-1991 Cameron county NTD cluster was superimposed on a background Cameron county NTD rate (16/10,000 live births) which is considerably higher than that generally noted in the United States (8-10/10,000 live births). These data suggest that genetic factors as well as transient environmental factors may contribute to the etiology of the NTDs. Furthermore, clinical and experimental evidence imply that allelic forms of genes involved with folate metabolism and/or transport may explain some of the observed variation in the NTD rates found across different populations. Two folate pathway genes were selected for evaluation in this study. The loci investigated included two known alleles of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, as well as the promoter region of the folate receptor-α (FR-α) gene. Odds ratios (ORs) for the C677T polymorphism in the MTHFR gene were 1.8 (CI 0.47- 6.8) for heterozygosity and 1.8 (CI 0.35-9.4) for homozygosity for the mutant 677T allele, relative to wildtype homozygotes. The odds ratio for the heterozygosity for the A1298C polymorphism in the same gene was 1.1 (CI 0.09- 14). No individuals homozygous for the 1298C allele were observed. The OR for heterozygosity of FR-α gene polymorphisms detected at nucleotide 762 and at nucleotides 610/631 was 1.4 and 0.7, respectively. Neither of the FR-α polymorphisms was observed in the homozygous condition. No statistically significant associations were observed for any of the polymorphisms examined, as the 95% confidence intervals for all of the ORs included one. However, the frequency of the MTHFR 677T allele in the largely Hispanic control group from Texas was significantly different from other populations (P < 0.005), and among the highest reported for any control populations examined. (C) 2000 Academic Press.