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

描述(由申请人提供)：这份建议书描述了一项为期3年的职业发展计划，以确立首席研究员Jill Waalen博士的学术生涯，重点是骨质疏松症的遗传流行病学。该项目旨在补充和发展瓦伦博士迄今通过研究生工作发展起来的研究技能和学术关系。作为斯克里普斯研究所的副研究员，瓦伦博士分析了一个现有数据库中的数据，该数据库中有4.1万名受试者参与了血色素沉着症的基因研究。血色沉着症是一种相对罕见的单基因疾病。由于这项工作，她已经在同行评议的期刊上发表了17篇以上的文章！该提议中的项目和职业规划将使最近被提升为助理教授终身教职的Waalen博士能够1)在招募10,000名新的研究对象进行基因分型研究的基础上，制定一项具有骨质疏松症作为常见多基因疾病模型的遗传流行病学的独立研究计划，这将为独立发起或与其他研究人员合作的其他遗传流行病学研究提供基础；2)接受流行病学研究的直接指导，以发展流行病学的学术基础。该奖项还将使她能够继续接受遗传和基因组分析实验室方法方面的额外培训，以及适用于研究常见多基因疾病的专门统计方法。目前提案中的具体项目涉及评估参与WNT/B-连环蛋白途径的基因的单核苷酸多态与骨密度的关系，这些基因包括低密度脂蛋白相关受体蛋白(LRP)-5和-6，来自Kaiser-San Diego健康评估诊所的10,000名65岁及以上的男性和女性，他们接受了双能X射线吸收测定(DXA)扫描。WNT/B-catenin途径刺激成骨细胞增殖，已被用于动物和人类研究中的骨密度测定。还将研究其他骨质疏松症相关基因的SNPs以及SNPs在基因-基因相互作用中的相互作用以及与环境因素的相互作用。作为职业奖的导师，斯克里普斯研究所(TSRI)的欧内斯特·比特勒博士将提供实验室空间和人员，以进行研究所需的大规模基因分型和基因分析方面的专业知识。作为该项目的共同导师，伊丽莎白·巴雷特-康纳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。TSRI的James Koziol博士和Nicholas Schork博士将提供多基因疾病分析的统计方法方面的额外专业知识。

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.