Genetics of Osteoporotic Fractures in Chinese

描述（由申请人提供）：我们请求资助，以支持/加强美国密苏里大学堪萨斯城分校（UMKC）和美国国立卫生研究院支持的PI与中国西安交通大学（XJTU）的年轻科学家在骨质疏松症遗传学领域的基础生物医学研究合作。在过去的4年里，该合作主要由中国提供资金支持，在骨质疏松症领域发表了20多篇论文，为中国的几位年轻科学家开辟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基因研究建立了基因分型、表型分型、基因表达谱和高性能计算平台。这项申请的资助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，合作院校西安交通大学将提供一笔配对基金，作为本申请（附录z）中拟议的合作项目的额外支持。骨质疏松症是一个主要的公共卫生问题，其主要特征是低骨密度（BMD）和易患骨质疏松性骨折（OF）。随着世界人口的老龄化，与of相关的死亡率和发病率日益成为西方和东方现代社会的沉重负担。到目前为止，人们已经做了大量的工作来鉴定与骨密度相关的基因，但很少有研究直接将OF作为研究表型。然而，OF是骨质疏松症的毁灭性后果，研究表明，与骨密度有关的基因可能并不都与OF有关。因此，揭示影响骨密度的遗传因素对OF也很重要，对了解骨质疏松的发病机制具有更大的意义。通过各种遗传和基因组方法，我们确定了2个重要的候选基因（RANK和CYP19）在白种人髋部骨密度中具有重要意义。然而，它们在BMD和/或of方面对中国人的意义是未知的。在本研究中，我们的假设是，与白种人髋部骨密度显著相关的基因也与中国人髋部骨密度和髋部骨质疏松性骨折（HF）相关。目的是通过在中文中检测白种人髋部骨密度相关基因的意义，鉴定中国人髋部骨密度和心衰相关基因。我们的具体目的是：1)检测与白种人髋部骨密度相关的两个基因RANK和CYP19与中国人群髋部骨密度和HF的相关性；2)从我们的母项目中选择另外6个骨质疏松候选基因，并测试它们与中国人群髋关节骨密度和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。经鉴定的对中国人髋部骨密度和心衰有显著影响的基因可作为基于基因型的预防和干预以降低心衰发生率的标记/靶点。作为PI与西安交大合作的国际支持，该项目将提供一个独特的机会，提高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过渡，并帮助提高中国骨质疏松症基础科学研究的整体水平。结合正在进行的对高加索人的研究，本项目将为世界上两大种族人群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，从而有助于解决全球骨质疏松症问题。表现地点(S)（组织、城市、州）密苏里大学堪萨斯城分校（UMKC），美国密苏里州堪萨斯城分校（UMKC）中国西安交通大学（XJTU），陕西西安耶鲁大学，康涅狄格州新天堂，美国康涅狄格州法明顿大学PHS 398（04/06版本）公共卫生相关性：骨质疏松症是一种主要以低骨密度（BMD）为特征的疾病，易使人增加骨质疏松性骨折（of）的风险。髋部OF是骨质疏松症最严重的后果。尽管人们已经做出了大量的努力来确定骨质疏松症的基因，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大量中国人样本中检测在白种人中发现的骨质疏松候选基因，来鉴定中国人的骨密度和of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。该结果将为两个主要种族人群（即白种人和中国人）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，从而有助于解决这一全球健康问题。所鉴定的基因可作为基因型特异性干预的靶点，降低of的发病率，最终改善骨质疏松症大流行的控制，提高中国人民的健康水平。PHS 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)