GENETIC EPIDIMOLOGY OF OSTEOPOROSIS

骨质疏松症是一种以低骨量和骨折为特征的慢性疾病。仅在美国，它就影响了2500多万男性和女性，相关的医疗保健支出每年接近130亿美元。目前提出的目标是确定负责骨质疏松症的人类基因，并加强我们对骨质疏松症病理生理的理解。使用外周DXA （pDXA）技术测量近端桡骨骨密度，这是骨质疏松症的一个强有力的预测指标，这项拟议的研究将在中国安庆的一个孤立人群中筛选15,000对年龄在40-64岁的同胞。这将产生762对具有极值的sib对（即，在协变量调整的近端桡骨骨密度的顶部或底部十分位数）。遗传分析的目标是：对所有762对esp（341对高一致性兄弟姐妹，327对低一致性兄弟姐妹，94对极不一致兄弟姐妹）及其亲本进行10 cm分辨率的全基因组扫描，并采用最新改进的Haseman-Elston方法进行连锁分析；[2]使用间距为1 cm的标记进行进一步的连锁分析，以达到具有显著LOD分数的饱和区域；[3]利用DHPLC开发单核苷酸多态性（SNP）标记，平均间隔为100 kb，覆盖进一步连锁研究证实的区域；[4]鉴定(a)先前报道的骨质疏松候选基因中的snp，以及参与骨质疏松主要生物学途径的基因：钙稳态、激素功能障碍、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)先前在染色体2p21.1-24区域发现的位置候选基因，以及(c)通过精细定位工作提示的位于染色体区域的位置候选基因；[5]对从这15000对40-64岁的同胞对中选择的800例（即低于第10百分位）和800例对照（即高于第90百分位）进行关联研究，利用snp在上述候选基因内或与上述候选基因存在强烈连锁不平衡；[6]通过对ESP家族进行传播不平衡测试（TDT）来检验病例对照分析的阳性结果。人类基因组计划（HGP）设定了一个新的目标，即到2003年底完成人类基因组序列。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绘制。这种与HGP的相互作用将大大加快我们基因发现过程的速度，并将为我们后续的基因评估和基因评价提供至关重要的指导。在确定候选变异后，可以对7000多名骨质疏松性骨折研究随访10年以上的女性以及健康和身体成分（HABC）和Mr. OS（男性骨质疏松症）研究的参与者进行骨质疏松症预测的临床价值测试。

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.