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Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2004 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 3, 323-328 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Bone mineral density (BMD) is under strong genetic control and a number of candidategenes have been associated with BMD. Both muscle strength and body weight are considered to beimportant predictors of BMD but far less is known about the genes affecting muscle strength andfat mass. The purpose of this study was to investigate the poly adenosine (A) repeat and the BsmISNP in the vitamin D receptor (VDR) in relation to muscle strength and body composition in healthywomen.

Design: A population-based study of 175 healthy women aged 20–39 years was used.

Methods: The polymorphic regions in the VDR gene (the poly A repeat and the BsmI SNP) were amplifiedby PCR. Body mass measurements (fat mass, lean mass, body weight and body mass index) andmuscle strength (quadriceps, hamstring and grip strength) were evaluated.

Results: Individuals with shorter poly A repeat, ss and/or absence of the linked BsmI restriction site(BB) have higher hamstring strength (ss vs LL, P ¼ 0.02), body weight (ss vs LL, P ¼ 0.049) andfat mass (ss vs LL, P ¼ 0.04) compared with women with a longer poly A repeat (LL) and/or thepresence of the linked BsmI restriction site (bb).

Conclusions: Genetic variation in the VDR is correlated with muscle strength, fat mass and bodyweight in premenopausal women. Further functional studies on the poly A microsatellite areneeded to elucidate whether this is the functionally relevant locus or if the polymorphism is in linkagedisequilibrium with a functional variant in a closely situated gene further downstream of the VDR30UTR.

Place, publisher, year, edition, pages
2004. Vol. 150, no 3, 323-328 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94305DOI: 10.1530/eje.0.1500323ISI: 000220540700011OAI: oai:DiVA.org:uu-94305DiVA: diva2:168109
Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2012-03-19Bibliographically approved
In thesis
1. Genetic Variability in Human Bone Phenotypes: The Vitamin D Receptor Gene and the Estrogen Receptor-α Cofactor RIZ Gene
Open this publication in new window or tab >>Genetic Variability in Human Bone Phenotypes: The Vitamin D Receptor Gene and the Estrogen Receptor-α Cofactor RIZ Gene
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Important candidate genes to human bone phenotypes are those involved in the regulation of hormonal action, such as the vitamin D receptor (VDR) and the estrogen receptor-α (ERα) genes and their cofactors. RIZ1 is a specific ERα cofactor proved to strongly enhance the function of the ERα.

The main focus of this thesis has been to study genetic variants in the VDR and RIZ genes and their associations to human bone phenotypes using candidate gene and functional approaches. Specifically, polymorphisms in the VDR 3’ untranslated region (UTR) and a deletion/insertion polymorphism of a proline in the RIZ gene were investigated.

The candidate gene approach was applied to large-scale population-based cohorts of pre-and post-menopausal women from Sweden and of elderly men from Sweden and Hong Kong. VDR 3’ UTR polymorphisms were associated with peak bone mass and body composition in young women. Further analysis of common VDR 3’ UTR haplotypes confirmed the association with BMD and risk of fractures in elderly men from Sweden and Hong Kong. The VDR polymorphisms were investigated for cis-acting effects, affecting allelic expression in the normal chromosomal context of human bone cells. The VDR allelic transcripts in the bone samples were unequally expressed, suggesting presence of regulatory variants in the 3’ UTR.

The polymorphism in the RIZ gene was strongly associated to BMD in pre- and postmenopausal women and in elderly men. The functional analyses included reporter constructs containing the RIZ polymorphic variants transfected in a cell line and its abilities in coactivating the ERα were examined. The variants were functionally different in coactivating the ERα-receptor complex.

To summarize, the results of this thesis show novel evidence for functional relevant polymorphisms in candidate genes to human bone phenotypes. These polymorphisms may contribute to the variation seen in BMD and risk of fractures in the population.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 135
Keyword
Medicine, Bone mineral density, candidate gene approach, polymorphism, the vitamin D receptor, the estrogen receptor α, RIZ1, cofactor, allelic imbalance, Medicin
Identifiers
urn:nbn:se:uu:diva-6784 (URN)91-554-6528-5 (ISBN)
Public defence
2006-05-05, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:15
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Available from: 2006-04-12 Created: 2006-04-12Bibliographically approved

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Ribom, Eva LLjunggren, ÖstenMallmin, HansKindmark, Andreas

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