Genetics of Osteoporotic Fractures in Chinese

描述（由申请人提供）：我们请求资助以支持/加强密苏里大学堪萨斯城分校（UMKC）美国和NIH支持的PI与中国Xi交通大学（XJTU）的年轻科学家之间在骨质疏松症遗传学领域的基础生物医学研究的持续合作。在过去的4年中，主要由中国资助的合作已经在骨质疏松症领域发表了超过20篇论文，为中国的几位年轻科学家提供了有前途的研究事业，并为骨质疏松症和其他人类复杂疾病的遗传研究建立了基因分型，表型，基因表达谱和高性能计算平台。该申请的资金将支持这种富有成效的工作关系的延续，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。如果申请获得资助，合作机构西安交通大学将提供一笔配对基金，作为对本建议书中建议的合作项目的额外支持（附录z）。骨质疏松症是一个主要的公共卫生问题，其主要特征是骨密度低和易发生骨质疏松性骨折。随着世界人口的老龄化，与OF相关的死亡率和发病率给西方和东方的现代社会带来越来越沉重的负担。到目前为止，已经做出了广泛的努力来确定与BMD相关的基因，很少有研究直接检查OF作为研究表型。然而，OF是骨质疏松症的破坏性结果，研究表明，对BMD有意义的基因可能并不都与OF相关。因此，揭示影响骨密度的遗传因素，对了解骨质疏松症的发病机制具有重要意义。通过各种遗传学和基因组学方法，我们确定了2个显著的候选基因（RANK和CYP 19）对高加索人的髋部BMD有重要意义。然而，他们的意义，中国方面的BMD和/或OF是未知的。在这项研究中，我们的假设是，在高加索人的髋部BMD显着的基因也与髋部BMD和髋部骨质疏松性骨折（HF）在中国。本研究的目标是通过检测中国人与高加索人髋部BMD相关的基因的显著性，确定中国人髋部BMD和HF的基因。我们的具体目的是：1）检测与白种人髋部BMD相关的RANK和CYP 19基因与中国人群髋部BMD和HF的相关性; 2）从我们的母项目中筛选出6个骨质疏松症候选基因，检测它们与中国人群髋部BMD和OF的相关性。本项目将有助于更好地了解中国人骨质疏松症的遗传基础。在中国人群中发现的与髋部BMD和HF相关的基因可能作为基于基因型的预防和干预的标志物/靶点，以降低HF的发病率。作为对PI与西安交通大学合作的国际支持，该项目将提供一个独特的机会，以增强中国合作青年科学家的研究经验和能力，加速他们向独立研究者的转变，并帮助提高中国骨质疏松症基础科研研究的整体水平。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种族人群的骨质疏松症遗传基础的种族特异性和/或普遍性提供新的见解，从而有助于解决骨质疏松症的全球问题。演出地点（机构、城市、州）美国密苏里州堪萨斯城密苏里大学（UMKC）中国陕西省Xi市Xi交通大学（XJTU）中国耶鲁大学，New Heaven，CT，美国康涅狄格大学，法明顿，CT，美国PHS 398（Rev. 04/06）公共卫生相关性：骨质疏松症是一种主要以骨矿物质密度（BMD）低为特征的疾病，易使患者发生骨质疏松性骨折（OF）的风险增加。髋部骨质疏松是骨质疏松症最具破坏性的结果。尽管人们已经做了大量的努力来鉴定骨质疏松症的相关基因，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OF本身作为骨质疏松症的表型。本项目的目的是通过在中国大样本中检测在白种人中发现的骨质疏松症候选基因，在中国人中发现不仅与BMD有关的基因，而且与OF有关的基因。本项目将有助于更好地了解中国人骨质疏松症的遗传基础。这些结果将为两个主要种族人群的骨质疏松症遗传决定的种族特异性和/或普遍性提供新的见解，即，因此，高加索人和中国人有助于解决这一全球健康问题。这些基因可能作为基因型特异性干预的靶点，以降低OF的发病率，最终改善骨质疏松症流行的控制，提高中国人民的健康水平。PHS 398（Rev. 04/06）

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)