Genetics of Osteoporotic Fractures in Chinese

描述(由申请人提供)：我们申请资助，以支持/加强美国密苏里大学堪萨斯城分校的PI和西安交通大学的青年科学家中国在骨质疏松遗传学领域的基础生物医学研究方面的持续合作。在过去的四年里，这项合作主要由中国资助，已在骨质疏松领域发表了20篇论文，为中国的几名年轻科学家奠定了光明的研究生涯，并为骨质疏松和其他人类复杂疾病的基因研究建立了基因分型、表型分析、基因表达谱分析和高性能计算平台。这项申请的资金将支持这种富有成效的工作关系的继续，这对中国骨质疏松症基础医学研究的发展至关重要，并加速中国年轻合作者的职业发展。如果这项申请获得资助，合作机构XJTU将提供一笔配对基金，作为对本提案中拟议的合作项目的额外支持(附录z)。骨质疏松症是一种主要的公共卫生问题，其主要特征是骨密度低和骨质疏松性骨折的易感性高。随着世界人口老龄化，与艾滋病相关的死亡率和发病率不断上升，给西方和东方的现代社会带来了越来越沉重的负担。到目前为止，人们已经做出了广泛的努力来确定与BMD相关的基因，但很少有研究直接检查作为研究表型的。然而，骨质疏松症的破坏性后果是骨质疏松症，研究表明，对骨密度有意义的基因可能并不都与骨质疏松症相关。因此，揭示影响骨密度的遗传因素，对于了解骨质疏松症的发病机制具有重要意义。通过不同的遗传学和基因组学方法，我们确定了两个显著影响高加索人髋部骨密度的候选基因(RANK和CYP19)。然而，就骨密度和/或骨密度而言，它们对中国人的意义尚不清楚。在这项研究中，我们的假设是高加索人的髋部骨密度显著的基因也与中国人的髋部骨密度和髋部骨质疏松性骨折(HF)相关。目的是通过用中文测试高加索人髋部骨密度相关基因的意义，以确定中国人髋部骨密度和心力衰竭的基因。我们的具体目标是：1)测试与高加索人髋部骨密度相关的RANK和CYP19两个基因在中国人群中与髋部BMD和HF的相关性；2)从我们的父母项目中选择另外6个骨质疏松症候选基因，并测试它们与中国人群中髋部骨密度和骨质疏松症的相关性。该项目将有助于更好地了解中国人骨质疏松症的遗传基础。这些与中国人髋部骨密度和心力衰竭显著相关的基因可作为基于基因的预防和干预措施的标志物/靶点，以降低心力衰竭的发病率。作为对国际骨质疏松研究所与西安交通大学合作的国际支持，该项目将为提升中国合作青年科学家的研究经验和能力，加快他们向独立调查人员的过渡，以及帮助提升中国骨质疏松基础科学研究的整体水平提供一个独特的机会。与正在进行的高加索人研究一起，该项目将为世界上两个主要民族人口的骨质疏松症遗传基础的种族特殊性和/或共性提供新的见解，从而有助于解决全球骨质疏松症问题。绩效网站(S)(组织，城市，州)美国密苏里州堪萨斯城大学，堪萨斯城，美国西安交通大学，陕西省西安，耶鲁大学，俄勒冈州新天市，康涅狄格州新天市，美国康涅狄格大学，法明顿，CT，美国PHS 398(04/06版)公共卫生相关性：骨质疏松症是一种主要以骨密度低为特征的疾病，容易使人患骨质疏松性骨折的风险增加。髋关节是骨质疏松症最具破坏性的后果.尽管人们对骨质疏松症的基因进行了广泛的研究，但大多数遗传学研究都集中在其替代表型BMD上，很少有研究直接将其本身作为骨质疏松症的表型。该项目的目标是通过在中国大样本中测试在高加索人中发现的骨质疏松症候选基因，不仅识别中国人的骨密度，而且还识别中国人的骨质疏松症基因。该项目将有助于更好地了解中国人骨质疏松症的遗传基础。这一结果将为高加索人和中国人这两个主要民族的骨质疏松症基因决定的种族特异性和/或共性提供新的见解，从而有助于解决这一全球健康问题。这些已确定的基因可作为针对中国的基因特异性干预的靶点，以降低骨质疏松症的发病率，最终改善骨质疏松症大流行的控制，增强人们的健康。小灵通398(04/06修订版)

DESCRIPTION (provided by applicant): We request funding to support/strengthen an ongoing collaboration in basic biomedical research in the area of genetics of osteoporosis between the US-based and NIH-supported PI at University of Missouri-Kansas City (UMKC) and young scientists in Xi'an Jiaotong University (XJTU), China. The collaboration, spanning over the past 4 years and supported mainly by funding from China, has resulted in >20 publications in the field of osteoporosis, seeded promising research careers for several young scientists in China, and established platforms for genotyping, phenotyping, gene expression profiling and high performance computing for genetic studies of osteoporosis and other human complex diseases. Funding of this application will support continuation of this productive working relationship, which is essential to the development of basic medical research of osteoporosis in China, and accelerate career development of the young Chinese collaborators. If this application is funded, a match-up fund will be granted from the collaborating institution, XJTU, to serve as additional support for the proposed collaborative project in this proposal (Appendix z). Osteoporosis is a major public health problem, mainly characterized by low bone mineral density (BMD) and high susceptibility to osteoporotic fractures (OF). With the aging of the world population, the mortality and morbidity associated with OF places an increasingly heavy burden on modern societies in the west as well the east. So far, extensive efforts have been made to identify genes associated with BMD, with few studies directly examining OF as the study phenotype. However, OF is the devastating outcome of osteoporosis and studies showed that genes significant for BMD may not all be relevant to OF. Therefore, disclosing the genetic factors influencing BMD, which are also important to OF, should be of greater significance for understanding the pathogenesis of osteoporosis. Through various genetic and genomic approaches, we identified 2 prominent candidate genes (RANK and CYP19) significant for hip BMD in Caucasians. However, their significance to Chinese in terms of BMD and/or OF is unknown. In this study, our HYPOTHESIS is that genes significant for hip BMD in Caucasians are also associated with hip BMD and hip osteoporotic fractures (HF) in Chinese. The GOAL is to identify the genes for hip BMD and HF in Chinese by testing in Chinese the significance of the genes associated with hip BMD in Caucasians. Our Specific Aims are 1) To test association with hip BMD and HF in Chinese population of two genes, RANK and CYP19, which were associated with hip BMD in Caucasians; 2) To select another six osteoporosis candidate genes to be identified from our parent projects and test their association with hip BMD and OF in the Chinese population. This project will contribute to better understanding the genetic basis of osteoporosis in Chinese. The genes identified significant for hip BMD and HF in Chinese may serve as markers/targets for genotype-based prevention and intervention to reduce the incidence of HF. As an international support for the PI's collaboration with XJTU, this project will provide a unique opportunity to enhance the research experience and capability of the collaborating young scientists in China, to accelerate their transition into independent investigators, and to help advance the overall level of basic scientific research of osteoporosis in China. Together with the ongoing studies in Caucasians, this project will provide novel insights into the ethnic specificity and/or generality of the genetic basis of osteoporosis for the two major ethnic populations in the world, thus contribute to addressing the global problem of osteoporosis. PERFORMANCE SITE(S) (organization, city, state) University of Missouri- Kansas City (UMKC), Kansas City, Missouri, USA Xi'an Jiaotong University (XJTU), Xi'an, Shaanxi Province, P.R. China Yale University, New Heaven, CT, USA University of Connecticut, Farmington, CT, USA PHS 398 (Rev. 04/06) PUBLIC HEALTH RELEVANCE: Osteoporosis is a disease mainly characterized by low bone mineral density (BMD), predisposing a person to an increased risk of osteoporotic fracture (OF). OF at hip is the most devastating outcome of osteoporosis. Though extensive efforts have been made to identify genes underlying osteoporosis, most of the genetic studies were focused on its surrogate phenotype BMD, and few studies directly study OF per se as the phenotype for osteoporosis. The goal of this project is to identify the genes not only for BMD but also for OF in Chinese, by testing in a large Chinese sample the osteoporosis candidate genes identified in Caucasians. This project will contribute to better understanding the genetic basis of osteoporosis in Chinese. The results will provide novel insights into the ethnic specificity and/or generality of the genetic determination of osteoporosis for the two major ethnic populations, i.e., Caucasians and Chinese, thus contribute to addressing this global health problem. The genes identified may serve as targets for genotype-specific interventions to reduce the incidence of OF, and eventually improve the control of osteoporosis pandemic and enhance people's health in China. PHS 398 (Rev. 04/06)