Morin I, Devlin AM, Leclerc D, Sabbaghian N, Halsted CH, Finnell R, Rozen R. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Molecular Genetics & Metabolism 2003 Jul;79(3):197-200.
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.
PMID: 12855225
Showing posts with label RFC-1. Show all posts
Showing posts with label RFC-1. Show all posts
Wednesday, August 1, 2007
Polymorphisms in genes involved in folate metabolism as risk factors for NTDs.
De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Cama A, Finnell RH, Andreussi L, Capra V. Polymorphisms in genes involved in folate metabolism as risk factors for NTDs. European Journal of Pediatric Surgery. 2001 Dec;11 Suppl 1:S14-7.
Moderate hyperhomocysteinemia in pregnant women has been associated with an increased risk of neural tube defects (NTDs). Periconceptional supplementation with multi-vitamins containing folic acid may normalize homocysteine metabolism and decrease the NTD risk. The C677 T variant of the MTHFR gene coding for a thermolabile enzyme has been described as the first genetic risk factor that accounts for a group of NTDs characterized by low maternal folate status and high homocysteine concentrations. Another common mutation of the same MTHFR gene, A1298 C, has also been described as an NTD risk factor. In addition to abnormal folate metabolism, anything that compromises the internalization of folate into the cell may be involved in the pathogenesis of NTDs. For this reason, a common polymorphism in the RFC-1 gene encoding the reduced folate carrier protein (A80 G) could also be an additional NTD risk factor. In the present study we examined the genotypic distributions and the allele frequencies of MTHFR A1298 C and RFC-1 A80 G polymorphisms in DNA samples from healthy Italian individuals and compared them to the frequencies observed in NTD cases and their parents. By means of restriction enzymatic analysis, we determined that the frequency of the mutated C allele of the A1298 C mutation was 0.25 among control individuals, which is in the range of that recently reported in other ethnic groups. However, we report that the mutant C allele frequencies are significantly higher among NTD cases and case mothers than among controls (0.39, 0.44, 0.25). Furthermore, for the RFC-1 A80 G mutation, we found that the frequency of the G allele of the RFC-1 mutation was 0.46 in the control population, suggesting that this is a common polymorphism in the Italian population. In spite of the high prevalence of the 80 G/G genotype among healthy subjects, we observed an increased frequency of the G allele in NTD-affected children, and their mothers and fathers. These preliminary results indicate that both the MTHFR and RFC-1 polymorphisms may play a role in NTD risk, at least in the Italian population. Further studies should be directed toward the evaluation of the level of risk conferred by the mutant MTHFR and RFC-1 genotypes, as well as the interaction between these genetic determinants and other nutritional and environmental factors.
PMID: 11813127
Moderate hyperhomocysteinemia in pregnant women has been associated with an increased risk of neural tube defects (NTDs). Periconceptional supplementation with multi-vitamins containing folic acid may normalize homocysteine metabolism and decrease the NTD risk. The C677 T variant of the MTHFR gene coding for a thermolabile enzyme has been described as the first genetic risk factor that accounts for a group of NTDs characterized by low maternal folate status and high homocysteine concentrations. Another common mutation of the same MTHFR gene, A1298 C, has also been described as an NTD risk factor. In addition to abnormal folate metabolism, anything that compromises the internalization of folate into the cell may be involved in the pathogenesis of NTDs. For this reason, a common polymorphism in the RFC-1 gene encoding the reduced folate carrier protein (A80 G) could also be an additional NTD risk factor. In the present study we examined the genotypic distributions and the allele frequencies of MTHFR A1298 C and RFC-1 A80 G polymorphisms in DNA samples from healthy Italian individuals and compared them to the frequencies observed in NTD cases and their parents. By means of restriction enzymatic analysis, we determined that the frequency of the mutated C allele of the A1298 C mutation was 0.25 among control individuals, which is in the range of that recently reported in other ethnic groups. However, we report that the mutant C allele frequencies are significantly higher among NTD cases and case mothers than among controls (0.39, 0.44, 0.25). Furthermore, for the RFC-1 A80 G mutation, we found that the frequency of the G allele of the RFC-1 mutation was 0.46 in the control population, suggesting that this is a common polymorphism in the Italian population. In spite of the high prevalence of the 80 G/G genotype among healthy subjects, we observed an increased frequency of the G allele in NTD-affected children, and their mothers and fathers. These preliminary results indicate that both the MTHFR and RFC-1 polymorphisms may play a role in NTD risk, at least in the Italian population. Further studies should be directed toward the evaluation of the level of risk conferred by the mutant MTHFR and RFC-1 genotypes, as well as the interaction between these genetic determinants and other nutritional and environmental factors.
PMID: 11813127
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