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- Title
Contribution of a common variant in the promoter of the 1-α-hydroxylase gene (CYP27B1) to fracture risk in the elderly.
- Authors
Clifton-Bligh, Roderick; Nguyen, Tuan; Au, Amy; Bullock, Martyn; Cameron, Ian; Cumming, Robert; Chen, Jian; March, Lyn; Seibel, Markus; Sambrook, Philip; Clifton-Bligh, Roderick J; Nguyen, Tuan V; Chen, Jian Sheng; March, Lyn M; Seibel, Markus J; Sambrook, Philip N
- 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 population-based 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 reporter gene 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 r² = 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.
- Subjects
RISK factors of fractures; GENETIC code; GENETIC polymorphisms; GENE expression; VITAMIN D; HARDY-Weinberg formula; FOLLOW-up studies (Medicine)
- Publication
Calcified Tissue International, 2011, Vol 88, Issue 2, p109
- ISSN
0171-967X
- Publication type
journal article
- DOI
10.1007/s00223-010-9434-4