Genetic Risk Factors for Coronary Artery Disease in Rheumatoid Arthritis

描述（由申请人提供）：本申请的长期目标是通过对遗传风险因素的研究，增加对类风湿关节炎（RA）中冠状动脉疾病（CAD）风险的炎症成分的理解。研究表明，传统的危险因素（如血脂异常）不能解释RA患者CAD风险比一般人群高出1.5-3.0倍。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）实现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)将遗传学的发展联系起来预测临床结果，CAD在RA中的应用；(2)采用多学科的“交叉”方法，利用生物信息学和新的分析技术来理解RA的一个重要临床问题。作为该项目的一部分，生物信息学方法可以应用于类风湿关节炎的未来研究。本项目的目的是开展一项遗传关联研究，以(1)确定与一般人群中传统危险因素和CAD风险相关的遗传标记与RA中CAD风险的关系，(2)研究发生RA的遗传危险因素，免疫失调标记是否也增加RA中CAD的风险，以及(3)测试被认为加速RA动脉粥样硬化的炎症介质是否增加CAD的风险。目标1-3的分析包括单SNP分析，以及目标1和目标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，并将其与临床+遗传数据相结合的模型进行比较。作为目标3的一部分，遗传信息对临床模型的贡献将通过预测建模和重新分类措施来确定。这项研究的结果可以为RA患者CAD的未来管理提供信息。2010年3月在哈佛大学公共卫生学院（HSPH）获得公共卫生硕士学位，2010年7月在布里格姆妇女医院（BWH）完成风湿病学研究，并一直担任风湿病学系医学讲师。她的近期职业目标是继续研究RA中CAD的遗传风险因素。她的长期职业目标是成为风湿病临床和遗传流行病学领域的独立研究者，具有利用电子病历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博士和风湿病学部遗传和基因组学主任Robert Plenge博士，将使她有效地在流行病学和遗传学之间架起桥梁。她的职业发展计划包括在遗传学、高级生物统计学和流行病学方面的持续培训，通过她的研究和教学课程的直接经验。廖博士就职于BWH、HSPH和Broad研究所丰富的研究和合作环境。

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. PUBLIC HEALTH RELEVANCE: Heart disease has been recognized as a serious complication of RA for at least five decades. However, little is known about whether RA itself, its treatment, or genetic factors lead to heart disease. This study would provide insight into our understanding of these factors in RA patients and can inform future treatment and prevention strategies for heart disease in RA.