ABSTRACT
A total of 523 subjects (297 females and 226 males) from the Canary Islands Nutrition Study (ENCA) were studied in order to examine the effect of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms, adjusted for age, serum (S)folate and Scobalamin levels, on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing® technology. The MTHFR 677Tallele was associated with increased tHcy concentrations only in males (P=0.005). The MTHFR 1298Callele was found to be associated with higher tHcy levels but similarly, only in males (P=0.025). The MTHFR 1793Aallele was associated with decreased tHcy concentrations in the younger males (P=0.042). A haplotypebased approach was marginally superior in explaining the genetic interaction of the MTHFR polymorphisms on tHcy plasma levels (R2 0.352 vs. 0.342 for a simple genotypebased approach). A nutrigenetic interaction between the MTHFR 677C>T genotype and Scobalamin on tHcy levels was demonstrated in both genders. The increase in tHcy was more pronounced with decreasing Scobalamin quintiles in 677TT homozygotes (P=0.005 for males and P=0.015 for females) than with decreasing Sfolate quintiles (P for trend not significant). It was concluded that genenutrient interactions may differ depending on the sex and age of the subjects. The transferability of genenutrient interactions from one community to others may therefore be limited not only by different food patterns but also by different ages, genders and genotype distributions.
Subject(s)
Homocysteine/blood , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Vitamin B 12/blood , Adult , Female , Gene Frequency , Genetic Association Studies , Haplotypes , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Sex Characteristics , SpainABSTRACT
The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR's) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.
Subject(s)
Epigenesis, Genetic , Folate Receptor 1/genetics , Hyperhomocysteinemia/genetics , Leukocytes/metabolism , Neural Tube Defects/genetics , Placenta/metabolism , Proton-Coupled Folate Transporter/genetics , Case-Control Studies , CpG Islands , DNA Methylation , Female , Folate Receptor 1/metabolism , Genotype , Homocysteine/blood , Humans , Hyperhomocysteinemia/metabolism , Infant, Newborn , Neural Tube Defects/metabolism , Polymorphism, Single Nucleotide , Pregnancy , Proton-Coupled Folate Transporter/metabolism , RNA, Messenger/metabolism , Replication Protein C/genetics , Replication Protein C/metabolism , Transcription, GeneticABSTRACT
BACKGROUND: Adolescents are vulnerable to increased plasma total homocysteine (tHcy) and to insufficient folate status. Folate status and Hcy metabolism are linked to cognitive functions, but academic achievement by adolescents has not been studied in this respect. OBJECTIVE: To assess a possible link between academic achievement in adolescents and tHcy and its determinants, dietary folate intake, MTHFR 677 TT homozygosity, and socioeconomic status (SES). SUBJECTS AND METHODS: A study of 386 Swedish adolescents aged 15 years in whom plasma tHcy and MTHFR 677C âT genotype were assayed. The sum of school grades in 10 core subjects obtained in the final semester of compulsory 9 years of schooling was used as outcome measure of academic achievement. Lifestyle and SES data were obtained from questionnaires. RESULTS: Academic achievement was strongly correlated to tertiles of tHcy (negatively; P = .023) and to tertiles of folate intake (positively; P < .001). Other significant predictors were gender, smoking, and SES (proxied by school, mother's education, and father's income). When these were controlled for, tertiles of folate intake (P < .002) but not tertiles of tHcy (P = .523) or MTHFR genotype remained significantly related to academic achievement. CONCLUSION: Folate intake had a positive association with academic achievement in the 15-year-olds, which was not attenuated by SES or MTHFR 677 TT homozygosity. These results provide new information that points to the importance of keeping a closer watch on folate status in childhood and adolescence. They may also have direct implications for school meal provisions, school teaching programs, and information to parents.
Subject(s)
Diet/methods , Educational Measurement/methods , Folic Acid/administration & dosage , Achievement , Adolescent , Cohort Studies , Educational Status , Female , Humans , Male , Sweden/epidemiologyABSTRACT
We have previously reported six novel mutations in the 5'-UTR of the gene for folate receptor-alpha (FOLR1). In our search for additional mutations we screened patients, referred for investigation of suspected dementia (DGM subgroup) by SSCP and DNA sequencing from the end of exon 1 to the first bases of intron 3. We found 4 sequence variations, FOLR1 g.1314G>A, g.1816delC, g.1841G>A, and g.1928C>T. Pyrosequencing genotyping assays were developed for all of them, and 389 active seniors (AS subgroup) and the 202 DGM patients were genotyped for these mutations. The frequency q of the mutated allele was, among the AS subjects, 0.068, 0.0026, 0.0026, and 0.024 respectively, and among the DGM subjects, 0.067, 0.0076, 0.0078, and 0.023. The g.1816delC and g.1841G>A mutations thus were more frequent in the DGM than in the AS subgroup, but the difference did not reach statistical significance. The mutated alleles, FOLR1 1816(-) and 1841A, always occurred together in the same subjects, suggestive of a rare double-mutant haplotype. The two common polymorphisms, FOLR1 g. 1314G>A and g.1928C>T seemed not to raise tHcy plasma levels, whereas the double-mutated g.1816(-)-g.1841A haplotype may possibly have a slight tHcy-raising effect. Thus, so far 8 novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. Only a few of the rare mutations may potentially be associated with raised plasma tHcy concentrations. No association with dementia was found.
Subject(s)
Carrier Proteins/genetics , Dementia/genetics , Exons/genetics , Mutation/genetics , Receptors, Cell Surface/genetics , Aged , Base Sequence , DNA Mutational Analysis , Female , Folate Receptor 1 , Folate Receptors, GPI-Anchored , Folic Acid/blood , Genetic Testing , Homocysteine/blood , Humans , Male , Molecular Sequence Data , Polymorphism, Single Nucleotide/geneticsABSTRACT
We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C, and 1793G>A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing technology. The MTHFR 677C>T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P<0.001 for both age groups) in both genders. The effect of MTHFR 1298A>C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C>T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C>T polymorphism. The common 1298A>C polymorphism had a minor elevating effect on tHcy, whereas the 1793G>A polymorphism had a lowering effect on tHcy.