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- Böttiger, Anna, 1977-
(author)
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Genetic variation in the folate receptor-alpha and methylenetetrahydrofolate reductase genes as determinants of plasma homocysteine concentrations
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and neurocognitive disease such as dementia. The B vitamins folate and B12 are the main de terminants of tHcy. tHcy concentration can also be affected by mutations in genes coding for receptors, enzymes and transporters important in the metabolism of Hcy. This thesis focuses on mutations in the genes for folate receptor-alpha and methylenetetrahydrofolate reductase (MTHFR) and the effect they have on tHcy concentrations. Six novel mutations in the gene for folate receptor-alpha were described in Paper I. Taken together they exist in a population with a prevalence of approximately 1% and thus are not unusual. There may be an association of –69dupA and –18C>T to tHcy but for the 25-bp deletion, –856C>T, –921T>C and –1043G>A there is probably no association to tHcy. Mutation screening was continued and four additional mutations, 1314G>A, 1816delC, 1841G>A and 1928C>T, were described in Paper II. The prevalences for the heterozygotes were between 0.5% and 13% in an elderly population. There was no significant difference in prevalence between the elderly subjects and patients with dementia. The 1816(–)-allele and the 1841A-allele were in complete linkage and the haplotype 1816(–)-1841A may possibly have a tHcy raising effect. The 1314G>A and 1928C>T mutations had no association to tHcy. The genotype prevalences and haplotype frequencies of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms were determined in a population sample of Swedish children and adolescents (Paper III). The MTHFR 677T-allele was associated with increased tHcy concentrations in both children and adolescents. A small elevating effect of the 1298C-allele and a small lowering effect of the 1793A-allele could be shown. In an epidemiological sample of adults from the Canary Islands, Spain, data for serum folate and vitamin B12 were used for a broader study of the nutrigenetic impact on tHcy (Paper IV). The 677T-allele had a significant tHcy increasing effect in men but not in women. The 1298C-allele had a minor elevating effect on tHcy in men with the 677CT genotype. It was not possible to document any effect of the 1793A-allele on tHcy due to its low prevalence. A slightly superior explanatory power for the genetic impact was obtained using the MTHFR haplotypes in the analysis compared to the MTHFR 677C>T genotype-based approach in both the Swedish children and adolescents and in the Spanish adults. Therefore MTHFR haplotypes should be considered when analysing the impact of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms on tHcy. Notwithstanding the large geographical distance between our study populations the haplotype composition is quite similar. The MTHFR 677T-allele is slightly more prevalent in Spain compared to Sweden but it has only an effect on tHcy in the Spanish men. Age, gender and factors linked to the ethnicity of the studied subjects, seem to be able to override the nutrigenetic impact of tHcy-raising genotypes or haplotypes in particular settings, such as in the Spanish women in our study. Gene-nutrient interactions on plasma tHcy levels thus may or may not exist in a certain population. The transferability of nutrigenetic findings may therefore be limited, and must be re-evaluated for each particular setting of age-gender-ethnicity.
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| 2. |
- Böttiger, Anna K., 1977-, et al.
(author)
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Association of total plasma homocysteine with methylenetetrahydrofolate reductase genotypes 677C > T, 1298A > C, and 1793G > A and the corresponding haplotypes in Swedish children and adolescents
- 2007
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In: International Journal of Molecular Medicine. - Athens, Greece : D.A. Spandidos. - 1107-3756 .- 1791-244X. ; 19:4, s. 659-665
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Journal article (peer-reviewed)abstract
- 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 (TM) 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.
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| 3. |
- Farkas, Sanja A., 1983-, et al.
(author)
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Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia
- 2013
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In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:3, s. 303-316
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Journal article (peer-reviewed)abstract
- 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 a (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.
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| 4. |
- Nilsson, Torbjörn K, et al.
(author)
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High folate intake is related to better academic achievement in Swedish adolescents
- 2011
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In: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 128:2, s. e358-e365
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Journal article (peer-reviewed)abstract
- 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 →T 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.
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| 5. |
- Nilsson, Torbjörn K., et al.
(author)
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MTHFR polymorphisms and serum cobalamin affect plasma homocysteine concentrations differentially in females and males
- 2014
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In: Molecular Medicine Reports. - : Spandidos Publications. - 1791-2997 .- 1791-3004. ; 10:5, s. 2706-2712
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Journal article (peer-reviewed)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 (5)-folate and S-cobalamin levels, on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing(R) 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 (R-2 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.
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