GENETIC EPIDIMOLOGY OF OSTEOPOROSIS

骨质疏松症是一种以骨量减少和骨折为特征的慢性疾病。仅在美国，就有2500多万男性和女性受到影响，相关的医疗保健支出每年接近130亿美元。目前这项建议的目的是确定人类导致骨质疏松症的基因，并加强我们对骨质疏松症的病理生理学的了解。使用外周DXA(PDXA)技术测量骨质疏松症的强预测指标--近端桡骨骨密度，这项拟议的调查将在中国安庆一个与世隔绝的人群中筛查15,000对年龄在40-之间的同胞。这将产生具有极值的762对同胞(即，在协变量调整的近端径向骨密度的顶部或底部的十分之一)。遗传分析的目标是：[1]对所有762个ESP(341对高一致性同胞对、327对低一致性同胞对和94对极不一致性同胞对)及其双亲进行10厘米分辨率的全基因组扫描，并使用最近改进的Haseman-Elston方法进行连锁分析；[2]使用间隔1厘米的标记进行进一步的连锁分析，以饱和具有显著LOD分数的区域；[3]使用DHPLC开发单核苷酸多态(SNP)标记，平均100kb间隔覆盖进一步连锁研究证实的区域；[4]确定(A)先前报道的骨质疏松候选基因以及与骨质疏松的主要生物学途径有关的基因：钙稳态、激素失调、成骨细胞和破骨细胞的发育和调节、软骨基质代谢和脂蛋白代谢；(B)先前确定的位于染色体2p21.1-24区域的位置候选基因，以及(C)精细定位工作所提示的位于染色体区域的位置候选基因；[5]利用上述候选基因内或与上述候选基因强连锁不平衡的SNPs，对从15,000对40-同胞中选出的800例(即10%以下)和800例对照(即90%以上)进行关联研究；以及[6]通过基于ESP家系的传递不平衡检验(TDT)来检验病例对照分析的阳性结果。人类基因组计划(HGP)提出了在2003年底前完成人类基因组测序的新目标。因此，当我们最初的基因组扫描和后续的连锁分析完成时，几乎所有的人类基因都将被测序和定位。与HGP的这种相互作用将极大地加快我们的基因发现过程的速度，并将为我们随后的基因评估和基因评估提供至关重要的指导。在确定了候选变异后，可以在7000多名特征良好的女性身上测试它们预测骨质疏松的临床价值，这些女性在骨质疏松骨折研究中进行了超过10年的跟踪调查，并参加了健康与身体成分(HABC)和男性骨质疏松症(MR OS)研究。

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.