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Novel gene implicated as a regulator of bone mineral density


Previously, Urano et al. employed an established technique to identify novel genes that could regulate bone mineral density (BMD), and could therefore be relevant to osteoporosis. They performed a genome-wide search in Japanese postmenopausal women to determine if any of 57,244 single nucleotide polymorphisms (SNPs) were associated with lower bone mineral density. Having identified 13 candidate SNPs, this study involved a second stage of analysis, and identified one key SNP – rs10514346, present in the GPR98 gene – for detailed investigation.

Women from the Japanese study population with the SNP in GPR98 had a significantly increased fracture risk (P=0.043) and retrospective analysis of Caucasian women from the Framingham Heart Study revealed that rs10514346 was also associated with lower BMD at the lumbar spine and the femoral neck in this second population. Further supportive evidence of the importance of GPR98 was provided by generating GPR98 knockout mice; these had significantly reduced femoral BMD at the age of 12 weeks. Furthermore, osteoblasts from these mice showed increased expression of Rankl and increased osteoclastic activity.

Editor's comment: The GPR98 gene maps to the quantitative trait locus for human femoral neck BMD on 5q14.3; moreover, SNPs in the GPR98 gene were shown to be associated with BMD in additional human samples. GPR98, whose function in bone remains unclear, could therefore be critical to the regulation of BMD in mice and humans.

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