GENETIC EPIDIMOLOGY OF OSTEOPOROSIS

骨质疏松症的遗传流行病学

• 批准号: 6876690
• 负责人: XIPING XU
• 金额: $ 23.8万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-06 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876690
• 关键词: China; bone density; clinical research; family genetics; genetic markers; genetic susceptibility; human subject; linkage disequilibriums; linkage mapping; osteoporosis; single nucleotide polymorphism

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.

骨质疏松症是一种以骨量低和骨折为特征的慢性疾病。 仅在美国就有超过 2500 万男性和女性受到影响，每年相关医疗保健支出接近 130 亿美元。 当前提案的目的是确定导致骨质疏松症的人类基因，并增强我们对骨质疏松症病理生理学的理解。 这项拟议的研究将利用外周 DXA (pDXA) 技术测量近端桡骨 BMD（骨质疏松症的有力预测因子），对中国安庆的一个孤立人群中 15,000 对 40-64 岁的同胞进行筛查。 这将产生 762 个具有极值的同胞对（即，在协变量调整的近端径向 BMD 的顶部或底部十分之一中）。 遗传分析的目的是： [1] 以 10 cM 分辨率对所有 762 个 ESP（341 个高一致性同胞对、327 个低一致性同胞对和 94 个极度不一致同胞对）及其父母进行全基因组扫描，并使用最近改进的 Haseman-Elston 方法进行连锁分析； [2] 使用间隔 1-cM 的标记进行进一步的连锁分析，以饱和具有显着 LOD 得分的区域； [3] 使用 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症候选基因以及参与骨质疏松症主要生物学途径的基因中的SNP：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) 先前在染色体区域 2p21.1-24 上确定的位置候选基因，以及 (c) 精细绘图工作建议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SNP，对从这15,000对40-64岁的同胞中选出的800个病例（即低于第10个百分位）和800个对照（即高于第90个百分位）进行关联研究； [6]通过基于 ESP 家族进行传递不平衡测试（TDT）来测试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，即在2003年底完成人类基因组测序。因此，当我们完成最初的基因组扫描和后续的连锁分析时，几乎所有人类基因都将被测序和作图。这种与人类基因组计划的相互作用将大大加快我们基因发现过程的速度，并为我们后续的基因评估和基因评价提供重要指导。 定义候选变异后，可以在 7,000 多名特征明确的女性中测试其预测骨质疏松症的临床价值，这些女性在骨质疏松性骨折研究中进行了 10 多年的跟踪，并在健康与身体成分 (HABC) 和 Mr. OS（男性骨质疏松症）研究的参与者中进行测试。