Genetic Risk Factors for Coronary Artery Disease in Rheumatoid Arthritis

描述（由申请人提供）：本提案的长期目标是通过研究遗传风险因素，增加对类风湿性关节炎（RA）中冠状动脉疾病（CAD）风险的炎症成分的了解。研究表明，传统的风险因素（例如，血脂异常）不能解释RA患者与一般人群相比额外1.5 - 3.0倍的CAD风险。该提案将在NIH信息学的基础设施内进行，以整合生物学和床边（i2b2），这是一项利用电子病历（EMR）进行发现研究的国家倡议。该项目直接解决了NIAMS的两个长期目标：（1）将遗传学的发展与预测RA的临床结局CAD联系起来，（2）采用多学科的“横切”方法，利用生物信息学和新的分析技术来理解RA的重要临床问题。作为该项目的一部分开发的生物信息学方法可以应用于类风湿关节炎的未来研究。 该项目的目的是进行遗传关联研究，以（1）确定与一般人群中传统风险因素和CAD风险相关的遗传标记如何与RA中的CAD风险相关，（2）研究发展RA的遗传风险因素，免疫失调的标记是否也增加RA中CAD的风险，以及（3）测试被认为加速RA中动脉粥样硬化的炎症介质，增加CAD风险。目标1 - 3的分析需要单一SNP分析，以及目标1和2中遗传风险评分（GRS）的应用。在每个目标中，将开发RA中CAD风险的临床模型，并与纳入临床+遗传数据的模型进行比较。作为目标3的一部分，将使用预测建模和重新分类措施来确定遗传信息对临床模型的贡献。这项研究的结果可以为RA患者CAD的未来管理提供信息。 凯瑟琳廖博士于2010年3月在哈佛公共卫生学院（HSPH）获得公共卫生硕士学位，于2010年7月在布莱根妇女医院（BWH）完成了她的流变学奖学金，并继续担任流变学系的医学讲师。她的近期职业目标包括追求她的建议，研究遗传风险因素的CAD在RA。她的长期职业目标是成为风湿性疾病临床和遗传流行病学领域的独立研究者，拥有利用EMR进行临床研究的专业知识。廖博士的导师，风湿病流行病学主任Elizabeth Karlson博士和风湿病科遗传学和基因组学主任Robert Plenge博士将使她能够有效地连接流行病学和遗传学。她的职业发展计划需要在遗传学，先进的生物统计学和流行病学的持续培训，通过她的研究和教学课程的直接经验。廖博士位于BWH，HSPH和Broad Institute的丰富研究和合作环境中。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to increase understanding of the inflammatory component of coronary artery disease (CAD) risk in rheumatoid arthritis (RA) through the study of genetic risk factors. Studies have demonstrated that traditional risk factors (e.g., dyslipidemia) cannot account for the additional 1.5-3.0 fold excess risk of CAD in RA patients compared to the general population. This proposal will be conducted within the infrastructure of the NIH informatics for integrating biology and the bedside (i2b2), a national initiative to harness the electronic medical record (EMR) to enable discovery research. This project directly addresses two long range goals of NIAMS by (1) linking developments in genetics to predict a clinical outcome, CAD in RA, and (2) by employing a multidisciplinary, "cross cutting" approach utilizing bioinformatics and novel analytical techniques to understand an important clinical question in RA. The bioinformatics methodology developed as part of this project can be applied to future research in rheumatoid arthritis. The aims of this project are to conduct a genetic association study to (1) determine how genetic markers associated with traditional risk factors and CAD risk in the general population relate to CAD risk in RA, (2) study whether genetic risk factors for developing RA, markers of immune dysregulation, also increase risk for CAD in RA, and (3) test whether inflammatory mediators thought to accelerate atherosclerosis in RA, increase risk for CAD. Analyses for aims 1-3 entail single SNP analyses, as well as application of genetic risk scores (GRS) in aims 1 and 2. In each aim a clinical model of risk for CAD in RA will be developed and compared to one incorporating clinical + genetic data. As part of aim 3, the contribution of genetic information to a clinical model will be determined using predictive modeling and reclassification measures. Findings from this study can inform the future management of CAD in RA patients. Dr. Katherine Liao received a Masters of Public Health degree at the Harvard School of Public Health (HSPH) in March 2010, completed her rheumatology fellowship at Brigham and Women's Hospital (BWH) in July 2010, and has stayed on as an Instructor in Medicine in the Division of Rheumatology. Her immediate career goal involves pursuit of her proposal to study genetic risk factors for CAD in RA. Her long term career goal is to become an independent investigator in the field of clinical and genetic epidemiology of the rheumatic diseases with expertise in utilizing EMRs for clinical research. Dr. Liao's mentors, Dr. Elizabeth Karlson, Director of Rheumatic Disease Epidemiology, and Dr. Robert Plenge, Director of Genetics and Genomics in the Division of Rheumatology, will allow her to effectively bridge epidemiology and genetics. Her career development plan entails ongoing training in genetics, advanced biostatistics and epidemiology, through direct experience from her research and didactic coursework. Dr. Liao is situated in the rich research and collaborative environment of BWH, HSPH, and the Broad Institute.