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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

基本信息

批准号：
8878177
负责人：
Katherine Phoenix Liao
金额：
$ 11.85万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878177
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 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 Medical Genetics 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 collaborative environment disorder risk experience genetic association genetic epidemiology genetic information genetic risk factor human PON1 protein improved insight instructor mortality multidisciplinary novel novel strategies predictive modeling risk variant treatment strategy

项目摘要

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）：该提案的长期目标是通过遗传风险因素的研究，增进对类风湿性关节炎（RA）中冠状动脉疾病（CAD）风险的炎症成分的了解。研究表明，传统的危险因素（例如血脂异常）无法解释 RA 患者的 CAD 风险比一般人群高出 1.5-3.0 倍。该提案将在 NIH 信息学基础设施内进行，以整合生物学和床边 (i2b2)，这是一项利用电子病历 (EMR) 来实现发现研究的国家举措。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 RA 中的 CAD 联系起来预测临床结果，以及 (2) 采用多学科、“交叉”方法，利用生物信息学和新颖的分析技术来理解 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) 确定一般人群中与传统风险因素和 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（免疫失调标记）是否也会增加 RA 中 CAD 的风险，以及 (3) 测试被认为会加速 RA 中动脉粥样硬化的炎症介质是否会增加 CAD 风险。目标 1-3 的分析需要进行单一 SNP 分析，以及在目标 1 和 2 中应用遗传风险评分 (GRS)。在每个目标中，将开发 RA 中 CAD 风险的临床模型，并将其与包含临床 + 遗传数据的模型进行比较。作为目标 3 的一部分，将使用预测模型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未来 RA 患者 CAD 的治疗提供参考。 Katherine Liao 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，并于 2010 年 7 月在布莱根妇女医院 (BWH) 完成风湿病学专科培训，并继续在风湿病科担任医学讲师。她近期的职业目标包括实现她的研究 RA 中 CAD 遗传风险因素的建议。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，拥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博士和风湿病科遗传学和基因组学主任Robert Plenge博士将帮助她有效地连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，在遗传学、高级生物统计学和流行病学方面进行持续培训。廖博士身处 BWH、HSPH 和 Broad 研究所丰富的研究和协作环境中。