IDENTIFYING POLYMORPHISMS IN THE LRP5 GENE IN BABOONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in the Low-density-lipoprotein-receptor-related protein 5 (Lrp5) in humans are responsible for skeletal disorders of both high and low bone mineral density (BMD). Inbred mouse studies have confirmed the effect of Lrp5 mutations on several aspects of bone quality. The extent to which variation in the Lrp5 gene contributes to normal variation in bone mineral density (BMD) in the general human population is currently the subject of intense investigation because of the large numbers of people affected by bone fragility diseases such as osteoporosis. Recent studies suggest that Lrp5 polymorphisms may indeed contribute to population level BMD variation. Mouse studies are serving to identify potential mechanisms of Lrp5 influence on bone, but extrapolation to humans of results from studies of such distantly related species can be problematic. The phylogenetic proximity of the baboon to humans and consequent similarities in skeletal physiology and metabolism make it an excellent model for studies of the genetics of human skeletal maintenance. A previous study shows significant evidence for a gene on chromosome 11q12-13 (the area of Lrp5) that affects normal variation in BMD in the baboon. We propose to sequence relevant portions of the Lrp5 gene in baboons to characterize genetic variation in this primate model for human bone maintenance and turnover. Exons 2,3,4,6,7,8, 9 and 10 of Lrp5 have been implicated in bone mass disorders and will be sequenced in 120 baboons for which we have existing data on BMD. The specific aims of this study are to: 1) sequence exons in Lrp5 known to affect BMD, 2) discover single nucleotide polymorphisms (SNPs) in these exons in SNPRC baboons, and 3) conduct analyses for tentative evidence of association between observed SNPs and BMD in the initial sample of baboons. This sequencing and SNP discovery will provide essential pilot data for a future application to the NIH to genotype another 556 animals for the SNPs identified in this study, thereby enabling a large scale association study to determine whether or not any of the discovered SNPs are associated with BMD variation.