Genetic markers of bone metabolism and bone disease

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Abstract
Genetic factors play an important role in the pathogenesis of several bone diseases. The the most important of these is osteoporosis - a common condition characterised by reduced bone mass and increased fracture risk, which affects up to 40% of women and 12% of men at some point during life. Twin and family studies suggest that up to 85% of the variance in bone mineral density is genetically determined. Clinical studies have identified several candidate genes which may be involved in this process. The vitamin D receptor gene (VDR) has been most widely studied, but the relationship between polymorphisms of the VDR and bone density has been found to be inconsistent and poorly reproducible in different populations. Polymorphisms in and around the genes encoding interleukin-6, tumour necrosis factor beta and the oestrogen receptor have also been associated with bone mass in some populations, but these have not been widely studied. In contrast, a functional polymorphism has been identified at a binding site for the transcription factor Sp1 in the collagen type I alpha 1 gene, which is associated with bone mass and osteoporotic fracture in several populations, suggesting that genotyping at this site may be of potential clinical value in the assessment of fracture risk. The importance of genetic factors in the regulation of bone mass, coupled with the ability to test for candidate polymorphisms in genomic DNA, indicates that genetic testing may play a role in the future assessment of osteoporotic fracture risk. The clinical value of this approach is at present unclear, but is likely to be an important area for future development as new polymorphisms are identified by genome wide searches and further analysis of candidate genes.