Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly

Clifton-Bligh, RJ; Nguyen, TV; Au, A; Bullock, M; Cameron, I; Cumming, R; Chen, JS; March, LM; Seibel, MJ; Sambrook, PN

Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly

Clifton-Bligh, RJ Nguyen, TV

Au, A Bullock, M Cameron, I Cumming, R Chen, JS March, LM Seibel, MJ Sambrook, PN

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Publication Type:: Journal Article
Citation:: Calcified Tissue International, 2011, 88 (2), pp. 109 - 116
Issue Date:: 2011-02-01

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Field	Value	Language
dc.contributor.author	Clifton-Bligh, RJ	en_US
dc.contributor.author	Nguyen, TV https://orcid.org/0000-0002-3246-6281	en_US
dc.contributor.author	Au, A	en_US
dc.contributor.author	Bullock, M	en_US
dc.contributor.author	Cameron, I	en_US
dc.contributor.author	Cumming, R	en_US
dc.contributor.author	Chen, JS	en_US
dc.contributor.author	March, LM	en_US
dc.contributor.author	Seibel, MJ	en_US
dc.contributor.author	Sambrook, PN	en_US
dc.date.available	2010-09-22	en_US
dc.date.issued	2011-02-01	en_US
dc.identifier.citation	Calcified Tissue International, 2011, 88 (2), pp. 109 - 116	en_US
dc.identifier.issn	0171-967X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/28733
dc.description.abstract	CYP27B1 encodes mitochondrial 1α-hydroxylase, which converts 25-hydroxyvitamin D to its active 1,25-dihydroxylated metabolite. We tested the hypothesis that common variants in the CYP27B1 promoter are associated with fracture risk. The study was designed as a populationbased genetic association study, which involved 153 men and 596 women aged 65-101 years, who had been followed for 2.2 years (range 0.1-5.5) between 1999 and 2006. During the follow-up period, the incidence of fragility fractures was ascertained. Bone ultrasound attenuation (BUA) was measured in all individuals, as were serum 25-hydroxyvitamin D and PTH concentrations; 86% subjects had vitamin D insufficiency. Genotypes were determined for the-1260C>A (rs10877012) and +2838T>C (rs4646536) CYP27B1 polymorphisms. A reportergene assay was used to assess functional expression of the-1260C>A CYP27B1 variants. The association between genotypes and fracture risk was analyzed by Cox's proportional hazards model. We found that genotypic distribution of CYP27B1-1260 and CYP27B1 + 2838 polymorphisms was consistent with the Hardy-Weinberg equilibrium law. The two polymorphisms were in high linkage disequilibrium, with D'= 0.96 and r 2 = 0.94. Each C allele of the CYP27B1-1260 polymorphism was associated with increased risk of fracture (hazard ratio = 1.34, 95% CI 1.03-1.73), after adjustment for age, sex, number of falls, and BUA. In transient transfection studies, a reporter gene downstream of the-1260(A)-containing promoter was more highly expressed than that containing the C allele. These data suggest that a common but functional variation within the CYP27B1 promoter gene is associated with fracture risk in the elderly. © The Author(s) 2010.	en_US
dc.relation.ispartof	Calcified Tissue International	en_US
dc.relation.isbasedon	10.1007/s00223-010-9434-4	en_US
dc.subject.classification	Endocrinology & Metabolism	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Genetic Predisposition to Disease	en_US
dc.subject.mesh	25-Hydroxyvitamin D3 1-alpha-Hydroxylase	en_US
dc.subject.mesh	Vitamin D	en_US
dc.subject.mesh	Risk	en_US
dc.subject.mesh	Genotype	en_US
dc.subject.mesh	Polymorphism, Genetic	en_US
dc.subject.mesh	Alleles	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Fractures, Bone	en_US
dc.subject.mesh	Promoter Regions, Genetic	en_US
dc.subject.mesh	Genetic Variation	en_US
dc.title	Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	88	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0903 Biomedical Engineering	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	88	en_US

Abstract:

CYP27B1 encodes mitochondrial 1α-hydroxylase, which converts 25-hydroxyvitamin D to its active 1,25-dihydroxylated metabolite. We tested the hypothesis that common variants in the CYP27B1 promoter are associated with fracture risk. The study was designed as a populationbased genetic association study, which involved 153 men and 596 women aged 65-101 years, who had been followed for 2.2 years (range 0.1-5.5) between 1999 and 2006. During the follow-up period, the incidence of fragility fractures was ascertained. Bone ultrasound attenuation (BUA) was measured in all individuals, as were serum 25-hydroxyvitamin D and PTH concentrations; 86% subjects had vitamin D insufficiency. Genotypes were determined for the-1260C>A (rs10877012) and +2838T>C (rs4646536) CYP27B1 polymorphisms. A reportergene assay was used to assess functional expression of the-1260C>A CYP27B1 variants. The association between genotypes and fracture risk was analyzed by Cox's proportional hazards model. We found that genotypic distribution of CYP27B1-1260 and CYP27B1 + 2838 polymorphisms was consistent with the Hardy-Weinberg equilibrium law. The two polymorphisms were in high linkage disequilibrium, with D'= 0.96 and r 2 = 0.94. Each C allele of the CYP27B1-1260 polymorphism was associated with increased risk of fracture (hazard ratio = 1.34, 95% CI 1.03-1.73), after adjustment for age, sex, number of falls, and BUA. In transient transfection studies, a reporter gene downstream of the-1260(A)-containing promoter was more highly expressed than that containing the C allele. These data suggest that a common but functional variation within the CYP27B1 promoter gene is associated with fracture risk in the elderly. © The Author(s) 2010.

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http://hdl.handle.net/10453/28733