Epidemiology of Genetic Risk Factors for Osteoporosis in Older Men and Women

描述（由申请人提供）：该提案描述了首席研究员Jill Waalen博士建立学术生涯的三年职业发展计划，重点是骨质疏松症的遗传流行病学。该项目旨在补充和建立Waalen博士迄今为止通过研究生工作开发的研究技能和学术关系。作为斯克里普斯研究所（The Scripps Research Institute）的一名助理研究员，瓦伦博士分析了血色素沉着症（一种相对罕见的单基因疾病）基因研究中已有的4.1万名受试者的数据。由于这项工作，她在同行评审的期刊上发表了超过17篇文章！该提案中的项目和职业规划将使最近晋升为助理教授的Waalen博士能够开发一个独立的遗传流行病学研究项目，其专长是将骨质疏松症作为一种常见的多基因疾病的模型，基于招募10,000名新受试者进行基因分型研究，这将为其他遗传流行病学研究提供基础。2)接受流行病学研究方面的直接指导，发展流行病学的学术基础。该奖项还将使她能够在遗传和基因组分析的实验室方法以及适用于研究常见多基因疾病的专门统计方法方面接受额外培训。当前提议的具体项目涉及评估wnt/B-catenin通路相关基因的单核苷酸多态性，包括ldl相关受体蛋白(LRP)-5和-6与骨密度的关系，这些基因来自Kaiser-San Diego健康评估诊所，年龄在65岁及以上的10,000名男性和女性接受了双能x射线吸收仪（DXA）扫描。在动物和人类研究中，wnt/ b -连环蛋白通路刺激成骨细胞增殖，并与骨矿物质密度的测定有关。其他骨质疏松相关基因的snp以及snp在基因间相互作用和与环境因素的相互作用也将被研究。作为职业奖的导师，斯克里普斯研究所（TSRI）的Ernest Beutler博士将为研究所需的大规模基因分型提供实验室空间和人员，并提供遗传分析方面的专业知识。作为该项目的共同导师，Elizabeth Barrett-Connor博士将提供骨质疏松症方面的专业知识，并在流行病学方法和骨相关候选基因的选择方面提供指导。Drs。TSRI的James Koziol和Nicholas Schork将在分析多基因疾病的统计方法方面提供额外的专业知识。

DESCRIPTION (provided by applicant): This proposal describes a 3-year career development plan for establishing the academic career of Principal Investigator, Dr. Jill Waalen, with a focus on the genetic epidemiology of osteoporosis. The project is designed to complement and build on the research skills and academic relationships Dr. Waalen has developed through post-graduate work to date. As a Research Associate at The Scripps Research Institute, Dr. Waalen has analyzed data from a pre-existing database of 41,000 subjects involved in a genetic study of hemochromatosis, a relatively rare, single gene disease. As a result of this work, she has published more than 17 articles in peer-reviewed journals! The project and career plan in this proposal will enable Dr. Waalen, who was recently promoted to the tenure-track position of Assistant Professor, 1) to develop an independent research program in genetic epidemiology with expertise in osteoporosis as a model of a common, multigenic disease, based on the recruitment of a new cohort of 10,000 subjects for genotyping studies which will provide the basis for other genetic epidemiology studies, both independently initiated and in collaboration with other researchers and 2) to receive direct mentoring in epidemiologic research to develop an academic base in epidemiology. The award will also enable her to pursue additional training in laboratory methods in genetic and genomic analysis and specialized statistical methods applicable to studying common, multigenic diseases. The specific project in the current proposal involves assessment of the association of single nucleotide polymorphisms of genes involved in the wnt/B-catenin pathway, including LDL-related receptor proteins (LRP)-5 and -6, with bone mineral density in 10,000 men and women age 65 and older recruited from the Kaiser-San Diego Health Appraisal Clinic who have undergone dual energy x- ray absorptiometry (DXA) scanning. The wnt/B-catenin pathway stimulates proliferation osteoblasts and has been implicated in determination of bone mineral density in animal and human studies. SNPs of other osteoporosis-related genes and interactions of SNPs in gene-gene interactions and with environmental factors will also be studied. As mentor for the career award, Dr. Ernest Beutler of The Scripps Research Institute (TSRI) will provide laboratory space and personnel for the large-scale genotyping required for the study and expertise in genetic analysis. As co-mentor for this project, Dr. Elizabeth Barrett-Connor will provide expertise in osteoporosis and guidance in epidemiologic methods and selection of bone-related candidate genes. Drs. James Koziol and Nicholas Schork of TSRI will provide additional expertise in statistical methods for analysis of multigenic diseases.