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Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences.ORCID iD: 0000-0002-2869-7239
Örebro University, School of Health and Medical Sciences.
2007 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 20, no 5, p. 653-662Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Athens, Greece: D.A. Spandidos , 2007. Vol. 20, no 5, p. 653-662
National Category
Medical and Health Sciences Geriatrics
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-3036PubMedID: 17912458OAI: oai:DiVA.org:oru-3036DiVA, id: diva2:136488
Available from: 2008-11-15 Created: 2008-11-15 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Genetic variation in the folate receptor-alpha and methylenetetrahydrofolate reductase genes as determinants of plasma homocysteine concentrations
Open this publication in new window or tab >>Genetic variation in the folate receptor-alpha and methylenetetrahydrofolate reductase genes as determinants of plasma homocysteine concentrations
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2008. p. 74
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 25
Keywords
Folate receptor-alpha, Folate, FOLR1, Haplotypes, Homocysteine, Methylenetetrahydrofolate reductase, MTHFR, Polymorphisms, Pyrosequencing®, SSCP
National Category
Clinical Science
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-2625 (URN)978-91-7668-642-3 (ISBN)
Public defence
2008-12-12, Wilandersalen, Universitetssjukhuset, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2008-11-15 Created: 2008-11-15 Last updated: 2017-10-18Bibliographically approved
2. Vascular mechanisms in dementia with special reference to folate and fibrinolysis
Open this publication in new window or tab >>Vascular mechanisms in dementia with special reference to folate and fibrinolysis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2009. p. 65
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 33
Keywords
dementia, Alzheimer’s disease, vascular dementia, folate, homocysteine, vitamin B12, CSF/Serum folate ratio, fibrinolysis, tPA, PAI-1
National Category
Geriatrics Medical and Health Sciences
Research subject
Geriatrics; Medicine
Identifiers
urn:nbn:se:oru:diva-7785 (URN)978-91-7668-682-9 (ISBN)
Public defence
2009-10-06, Bohmanssonsalen, Universitetssjukhuset Örebro, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2009-09-02 Created: 2009-09-01 Last updated: 2017-10-18Bibliographically approved

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Böttiger, Anna K.Hagnelius, Nils-OlofNilsson, Torbjörn K.

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