GENETIC EPIDIMOLOGY OF OSTEOPOROSIS

骨质疏松症的遗传流行病学

• 批准号: 7119915
• 负责人: XIPING XU
• 金额: $ 53.67万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119915
• 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.

骨质疏松症是一种慢性疾病，其特征是低骨量和骨折。 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接近130亿美元/年。 目前的建议的目的是确定人类基因负责骨质疏松症，并提高我们对骨质疏松症的病理生理学的理解。 利用外周DXA（pDXA）技术测量桡骨近端BMD，这是骨质疏松症的一个强有力的预测因素，这项拟议的调查将在中国安庆的一个隔离人群中筛选15,000对40-64岁的同胞对。 这将产生762个具有极值的同胞对（即，在协变量调整的近端桡骨BMD的顶部或底部十分位数中）。 遗传分析的目的是：[1]以10 cM分辨率对所有762个ESP进行全基因组扫描（341对高度一致同胞对，327对低度一致同胞对，94对极不一致同胞对）及其亲本，并采用最近改进的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，以使具有显著LOD分数的区域饱和;[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上鉴定的位置候选者，和（c）通过精细作图努力建议的位于染色体区域中的位置候选基因; [5]对800个病例进行关联研究（即，低于第10百分位数）和800个对照（即，第90百分位数以上）;[6]通过基于ESP家族进行传递不平衡检验（TDT）来检验来自病例对照分析的阳性结果。 人类基因组计划（HGP）制定了一个新的目标，即到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，几乎所有的人类基因都将被测序和定位。这种与HGP的相互作用将大大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价提供重要的指导。 在确定候选变体后，可以在骨质疏松性骨折研究中随访超过10年的7，000多名特征良好的女性以及健康和身体成分（HABC）和OS先生（男性骨质疏松症）研究的参与者中测试其预测骨质疏松症的临床价值。

项目成果

Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women.

• DOI: 10.1093/ajcn/83.1.146
• 发表时间: 2006
• 期刊: The American journal of clinical nutrition
• 作者: Y. Hsu;S. Venners;H. Terwedow;Yan Feng;T. Niu;Zhiping Li;N. Laird;Joseph D. Brain;S. Cummings;M. Bouxsein;C. Rosen;Xiping Xu

Candidate genes for osteoporosis. Therapeutic implications.

骨质疏松症的候选基因。

• DOI: 10.2165/00129785-200101010-00002
• 发表时间: 2001
• 期刊: American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
• 作者: Niu,T;Xu,X
• 通讯作者: Xu,X

Impact of seafood and fruit consumption on bone mineral density.

• DOI: 10.1016/j.maturitas.2006.05.001
• 发表时间: 2007-01
• 期刊: Maturitas
• 影响因子: 4.9
• 作者: P. Zalloua;Y. Hsu;H. Terwedow;T. Zang;Di Wu;Genfu Tang;Zhiping Li;X. Hong;S. Azar;Bin-yan Wang;M. Bouxsein;Joseph D. Brain;S. Cummings;C. Rosen;Xiping Xu