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A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynaecology, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Competence Centre On Reproductive Medicine and Biology, Tartu, Estonia.
Department of Clinical Sciences, School of Health Sciences, University of Las Palmas of Gran Canaria, Las Palmas, Spain.
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2012 (English)In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 39, no 4, p. 4471-4478Article in journal (Refereed) Published
Abstract [en]

Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-alpha being the major high-affinity receptor. Rare genetic variations in exons of the FR-alpha gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G > A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B-12 levels and MTHFR 677C > T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.

Place, publisher, year, edition, pages
Dordrecht, Netherlands: Springer, 2012. Vol. 39, no 4, p. 4471-4478
Keywords [en]
Folate receptor, FOLR1, Haplotype, Homocysteine, Polymorphism
National Category
Medical and Health Sciences Biochemistry and Molecular Biology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-22311DOI: 10.1007/s11033-011-1236-xISI: 000301108500127PubMedID: 21938430Scopus ID: 2-s2.0-84863006599OAI: oai:DiVA.org:oru-22311DiVA, id: diva2:513411
Note

Funding Agencies:

Estonian Ministry of Education and Science 

Enterprise Estonia 

Nyckelfonden, Örebro 

Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2018-09-13Bibliographically approved

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Nilsson, Torbjörn K.

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