Genetic Risk Factors for Coronary Artery Disease in Rheumatoid Arthritis

类风湿性关节炎中冠状动脉疾病的遗传危险因素

• 批准号: 8493997
• 负责人: Katherine Phoenix Liao
• 金额: $ 13.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493997
• 关键词: Accounting; Address; Alleles; Animal Model; Antirheumatic Agents; Atherosclerosis; Bioinformatics; Biology; Biometry; C-reactive protein; Cardiovascular Diseases; Cholesterol; Clinical; Clinical Research; Complication; Computerized Medical Record; Coronary Arteriosclerosis; Data; Development; Development Plans; Diagnosis; Disease; Disease Outcome; Dyslipidemias; Environment; Enzymes; Epidemiology; Event; Fellowship; Foam Cells; Future; General Population; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genomics; Genotype; Goals; Heart Diseases; Hospitals; Human; Human Genetics; Immune; Immunologic Markers; Individual; Inflammation; Inflammation Mediators; Inflammatory; Informatics; Institutes; Lead; Link; Low Density Lipoprotein oxidation; Master of Public Health; Measures; Mediator of activation protein; Medicine; Mentors; Methodology; Modeling; Modification; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevention strategy; Proteins; Public Health Schools; Publishing; Research; Research Infrastructure; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatology; Risk; Risk Factors; Role; Steroids; Techniques; Testing; Training; United States National Institutes of Health; Woman; atherogenesis; career; career development; clinical epidemiology; cohort; disorder risk; experience; genetic association; genetic epidemiology; genetic risk factor; human PON1 protein; improved; insight; instructor; mortality; multidisciplinary; novel; novel strategies; predictive modeling; treatment strategy

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.

描述(由申请人提供)：这项建议的长期目标是通过对遗传风险因素的研究，增加对类风湿性关节炎(RA)冠状动脉疾病(CAD)风险的炎症成分的了解。研究表明，与普通人群相比，传统的危险因素(如血脂异常)不能解释RA患者额外1.5-3.0倍的额外冠心病风险。这项提议将在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，以预测临床结果--类风湿性关节炎的CAD；(2)利用生物信息学和新的分析技术，采用多学科的“交叉”方法来理解类风湿性关节炎的重要临床问题。作为该项目的一部分开发的生物信息学方法可以应用于未来类风湿性关节炎的研究。本项目的目的是进行一项遗传关联研究，以(1)确定与传统危险因素和普通人群中的CAD风险相关的遗传标记如何与RA的CAD风险相关；(2)研究发生RA的遗传风险因素(免疫失调的标记)是否也会增加RA的CAD风险；以及(3)测试炎症介质是否被认为加速了RA的动脉粥样硬化，增加了CAD的风险。对于AIMS 1-3的分析需要进行单SNP分析，以及在AIMS 1和2中应用遗传风险评分(GRS)。在每个目标中，将建立RA冠心病风险的临床模型，并将其与结合临床+遗传数据的模型进行比较。作为目标3的一部分，将使用预测性建模和重新分类措施来确定遗传信息对临床模型的贡献。这项研究的发现可以为未来RA患者的CAD治疗提供参考。廖博士于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)完成风湿病研究，并一直在风湿科担任内科讲师。她的直接职业目标包括追求她的建议，即研究RA中冠心病的遗传风险因素。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员，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伊丽莎白·卡尔森博士和风湿病科遗传学和基因组学主任罗伯特·普伦格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通过她的研究和教学课程的直接经验，在遗传学、高级生物统计学和流行病学方面进行持续的培训。廖博士座落在华威卫生研究院、华威卫生研究院和远大研究所丰富的研究和协作环境中。