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: 8190112
• 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/8190112
• 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. 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.

描述（由申请人提供）：该提案的长期目标是通过研究遗传危险因素来增加类风湿关节炎（RA）中对冠状动脉疾病（CAD）风险的炎症成分的了解。研究表明，与普通人群相比，RA患者的传统危险因素（例如血脂血症）无法解释RA患者CAD的额外1.5-3.0倍过多的风险。该提案将在NIH信息学基础设施中进行，用于整合生物学和床边（I2B2），这是一项利用电子医疗记录（EMR）的国家计划，以启用发现研究研究。该项目通过（1）通过（1）将遗传学的发展链接到NIAMS的两个远距离目标，以预测临床结果，RA中的CAD和（2）通过采用多学科的“交叉切割”方法，利用生物信息学和新颖的分析技术来了解RA中的重要临床问题。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。 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.目标1-3的分析需要单个SNP分析，以及在目标1和2中的遗传风险评分（GRS）的应用。在每个目标中，将开发RA中CAD的临床风险模型，并将其与结合临床 +遗传数据的临床风险模型进行比较。作为AIM 3的一部分，将使用预测建模和重新分类措施确定遗传信息对临床模型的贡献。这项研究的发现可以告知RA患者的CAD的未来管理。 Katherine Liao博士于2010年3月在哈佛公共卫生学院（HSPH）获得公共卫生学位硕士学位，并于2010年7月在Brigham and妇女医院（BWH）完成了风湿病学研究金，并已在风湿病学系担任医学教练。她的直接职业目标涉及追求她研究RA中CAD遗传危险因素的提议。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，并在利用EMR用于临床研究方面具有专业知识。风湿病流行病学主任莉奥（Liao）的导师伊丽莎白·卡尔森（Elizabeth Karlson）博士和风湿病学系的遗传学和基因组学主任罗伯特·普兰格（Robert Plenge）博士将有效地桥接流行病学和遗传学。她的职业发展计划需要通过她的研究和教学课程的直接经验进行遗传学，高级生物统计学和流行病学的持续培训。 Liao博士位于BWH，HSPH和Broad Institute的丰富研究和协作环境中。 公共卫生相关性：至少五十年来，心脏病一直被认为是RA的严重并发症。但是，关于RA本身，其治疗或遗传因素会导致心脏病。这项研究将洞悉我们对RA患者这些因素的理解，并可以为RA中心脏病的未来治疗和预防策略提供信息。