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 (R 2 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.
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.
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.
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 S‑cobalamin levels, on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing® technology. The MTHFR 677T‑allele was associated with increased tHcy concentrations only in males (P=0.005). The MTHFR 1298C‑allele was found to be associated with higher tHcy levels but similarly, only in males (P=0.025). The MTHFR 1793A‑allele was associated with decreased tHcy concentrations in the younger males (P=0.042). A haplotype‑based 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 genotype‑based approach). A nutrigenetic interaction between the MTHFR 677C>T genotype and S‑cobalamin on tHcy levels was demonstrated in both genders. The increase in tHcy was more pronounced with decreasing S‑cobalamin quintiles in 677TT homozygotes (P=0.005 for males and P=0.015 for females) than with decreasing S‑folate quintiles (P for trend not significant). It was concluded that gene‑nutrient interactions may differ depending on the sex and age of the subjects. The transferability of gene‑nutrient 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.
The 776C>G polymorphism of the Transcobalamin II gene is located in a GC-rich region and TaqMan real-time polymerase chain reaction (PCR) does not yield satisfactory genotyping results. We therefore hypothesized that a method based on DNA sequencing would be needed for this single nucleotide polymorphism (SNP) analysis; Pyrosequencing technology was tested for this purpose. A Pyrosequencing protocol was developed, optimized and applied to a sample of 389 Swedish senior citizens. The three genotypes CC, CG, and GG consistently yielded typical programs that were readily distinguishable from each other. The prevalence of the mutated allele in the studied Swedish population was q=0.445. It is concluded that the TC II 776C>G polymorphism can be reliably genotyped by Pyrosequencing technology.
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