GENETIC EPIDIMOLOGY OF OSTEOPOROSIS

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Osteoporosis is a chronic disorder characterized by low bone mass and fractures. It affects more than 25 million men and women in the United States alone, where related health care expenditures approach 13 billion/dollars year. The objective of the current proposal is to identify human genes responsible for osteoporosis and to enhance our understanding of the pathophysiology of osteoporosis. Using peripheral DXA (pDXA) technology to measure proximal radial BMD, a strong predictor for osteoporosis, this proposed investigation will screen 15,000 sib pairs aged 40-64 years in an isolated population in Anqing, China. This will yield 762 sib pairs with extreme values (i.e., in the top or bottom decile of covariate-adjusted proximal radial BMD). The genetic analyses will aim: [1] to perform a total genomic scan at a 10-cM resolution on all 762 ESPs (341 high concordant sib pairs, 327 low concordant sib pairs, and 94 extremely discordant sib pairs) and their parents, and to carry out linkage analysis using the recently improved Haseman-Elston method; [2] to perform further linkage analysis using markers spaced 1-cM apart to saturate regions with significant LOD scores; [3] to develop single nucleotide polymorphism (SNP) markers using DHPLC with an average 100-kb interval covering the regions confirmed by further linkage studies; [4] to identify SNPs in (a) previously reported osteoporosis candidate genes as well as genes involved in major biological pathways of osteoporosis: calcium homeostasis, hormonal dysfunction, osteoblast and osteoclast development and regulation, cartilage matrix metabolism and lipoprotein metabolism; (b) previously identified positional candidates on chromosomal region 2p21.1-24, and (c) positional candidate genes residing in the chromosomal regions suggested by fine mapping efforts; [5] to perform an association study on 800 cases (i.e., below the 10th percentile) and 800 controls (i.e., above the 90th percentile) selected from these 15,000 sib pairs aged 40-64 utilizing SNPs within or in strong linkage disequilibrium with the above candidate genes; and [6] to test the positive findings from the case-control analysis by performing transmission disequilibrium tests (TDT) based on the ESP families. The Human Genome Project (HGP) has set a new goal to complete the human genome sequence by the end of 2003. Therefore, by the time our initial genome scan and the follow-up linkage analyses are completed, almost all human genes will be sequenced and mapped. Such an interaction with HGP will greatly accelerate the speed of our gene discovery process and will provide crucial guidance for our consequent gene assessment and gene evaluation. After candidate variants have been defined, their clinical value for prediction of osteoporosis could be tested in over 7,000 well characterized women who have been followed for over 10 years in the Study of Osteoporotic Fractures and in participants of the Health and Body Composition (HABC) and Mr. OS (Osteoporosis in Men) studies.