Family History, Genes, Environment and G X E Interaction in Predicting RA Risk

家族史、基因、环境和 G X E 相互作用在预测 RA 风险中的作用

• 批准号: 8078134
• 负责人: ELIZABETH W KARLSON
• 金额: $ 15.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078134
• 关键词: ARHGEF5 gene; Address; Age; Air Pollution; Algorithms; Alleles; Antibodies; Antigens; Area; Autoantibodies; Autoimmune Diseases; Behavioral; Bioinformatics; Biological Markers; Biology; Body mass index; Breathing; Calibration; Candidate Disease Gene; Case-Control Studies; Cigarette; Citrulline; Classification; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Code; Cohort Studies; Collection; Computerized Medical Record; Cox Proportional Hazards Models; DNA; DNA Markers; Data; Data Set; Databases; Development; Diagnosis; Diagnostic; Discrimination; Disease; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epidemiology; Epitopes; Etiology; Exposure to; Family; Family Study; Family history of; Female; First Degree Relative; Funding; Future; Gender; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Grant; HLA-DR4 Antigen; HLA-DRB1; Healthcare; Heterogeneity; Hormonal; Hormones; Human Genome; ICD-9; Immune; Immunity; Immunologist; Incidence; Individual; Inflammatory; Informatics; Institution; Interdisciplinary Study; Interview; K-Series Research Career Programs; Laboratories; Lead; Life; Link; Logistic Models; Logistic Regressions; Lung; Measures; Menopausal Status; Mentors; Meta-Analysis; Methods; Methotrexate; Mid-Career Clinical Scientist Award (K24); Minerals; Mining; Modeling; Modification; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Language Processing; Notification; Occupational; PTPN22 gene; Paper; Particulate; Particulate Matter; Pathogenesis; Patients; Peer Review; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Physicians; Pollution; Population; Predisposition; Prevention; Prevention strategy; Principal Investigator; Publishing; Race; Recording of previous events; Records; Reproductive History; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Support; Research Training; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Risk Factors; STAT4 gene; Sampling; Siblings; Signs and Symptoms; Single Nucleotide Polymorphism; Smoking; Socioeconomic Status; Statistical Methods; Stratification; Subgroup; Surface; Sushi Domain; Sweden; Symptoms; System; Systemic Lupus Erythematosus; TNF receptor-associated factor 1; Techniques; Testing; Text; Time; Toxic Environmental Substances; Training; Training Programs; Travel; Tumor Necrosis Factor-alpha; United States; United States National Institutes of Health; Variant; Woman; Work; abstracting; adalimumab; base; case control; cigarette smoking; cohort; cost effective; cyclic citrullinated peptide; cytokine; epidemiology study; experience; gene environment interaction; genetic analysis; genetic association; genetic epidemiology; genetic risk factor; genetic technology; genetic variant; genome wide association study; high risk; improved; inclusion criteria; infliximab; innovation; insight; meetings; men; multidisciplinary; novel; parity; patient oriented research; pre-clinical; predictive modeling; prevent; prevention clinical trial; programs; reproductive; research study; response; sample collection; sex; toxin metabolism; trafficking; treatment response; tumor necrosis factor-alpha inhibitor

DESCRIPTION (provided by applicant): Since receiving the K24 award, I have established a successful clinical research and training program in patient-oriented research (POR) in rheumatic disease with a focus on genetic, biomarker, and environmental risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). I continue to have independent grant support, and have mentored 15 new clinical investigators who have published 25 peer- reviewed papers during the K24 period. Three mentees have received NIH K awards and one has received an NIH R01. With renewal of the K24, I would continue to have protected time to devote to this program that has a unique training environment and an array of important POR projects. Genetic and environmental epidemiology studies have produced convincing evidence for multiple alleles and exposures as RA risk factors. A strong gene-environment (GXE) interaction between HLA-DRB1 alleles and smoking has been demonstrated for risk of the immune phenotype of CCP positive RA but not CCP negative RA. As CCP antibodies occur years before RA onset, I hypothesize that this interaction induces anti-citrulline immunity, a critical step in RA pathogenesis. These findings emphasize the need to study genes, environment and immunity with careful phenotyping. Family history encompasses unmeasured genetic and environmental risk, yet is not measured accurately in other studies including those in my research portfolio. Specific aims are to: 1) Maintain and expand my clinical research training program by mentoring new clinical investigators in POR in rheumatic diseases; 2) Enrich my comprehensive POR program to study family history, genetic, and environmental predictors in the etiology of RA using a new collection of RA cases and controls from Partners HealthCare; 2a) Collect family history data and environmental exposure data concerning smoking and reproductive factors on 1,500 RA patients and 4,500 age- and gender-matched controls by utilizing natural language processing (NLP) queries of electronic medical records; 2b: Examine genetic risk factors, environmental risk factors and GXE in predicting immune phenotypes of RA: RA with and without CCP antibodies (CCP?), and RA with and without rheumatoid factor antibodies (RF?); and 2c: Apply this comprehensive risk model to RA cases and controls and to subsets of RA stratified by specific immune phenotypes and stratified by family history of RA and other autoimmune diseases. The proposed study will leverage the NIH funded Informatics for Integrating Biology and the Bedside study that used an advanced informatics infrastructure to extract clinical data on RA diagnostic features through database mining and NLP. A highly specific algorithm was used to identify RA cases and collect samples from cases and controls. The NLP techniques will be used to extract risk factor data from clinical notes. This proposal builds on my strong track record of POR, extending the work to add family history from a new case-control collection, validate data by patient interview, and develop predictive models for risk of RA that can be used to select high risk individuals for future RA prevention trials.

描述（由申请人提供）：自获得K24奖以来，我就建立了一项成功的风湿性疾病研究（POR）的临床研究和培训计划，重点是遗传性，生物标志物和类风湿性关节炎（RA）和全身性红细胞的环境风险因素（SLE）。我继续获得独立的赠款支持，并指导了15名新的临床研究人员，他们在K24期间发表了25份同行评审的论文。三名受训者获得了NIH K奖，其中一名获得了NIH R01。随着K24的续签，我将继续有保护这个计划的时间，该计划具有独特的培训环境和一系列重要的POR项目。遗传和环境流行病学研究已经为RA风险因素提供了令人信服的证据。 HLA-DRB1等位基因和吸烟之间的强大基因环境（GXE）相互作用已被证明是因为CCP阳性RA的免疫表型的风险，而不是CCP阴性RA。由于CCP抗体发生在RA发作之前的几年中，我假设这种相互作用诱导抗西鲁氨酸免疫，这是RA发病机理的关键步骤。这些发现强调了通过仔细表型研究基因，环境和免疫力的必要性。家族史包括未衡量的遗传和环境风险，但在包括我的研究组合中的其他研究中未能准确衡量。具体目的是：1）通过指导风湿性疾病的POR新临床研究人员来维持和扩展我的临床研究培训计划； 2）丰富了我的全面POR计划，以研究RA的病因中的家族史，遗传和环境预测因素，并使用合作伙伴Healthcare的RA病例和控制措施集合； 2A）通过利用自然语言处理（NLP）电子记录查询，收集有关1,500名RA患者和4,500例年龄和性别匹配的对照的家庭历史数据和环境暴露数据； 2b：在预测有或没有CCP抗体（CCP？）的RA的免疫表型时，检查遗传危险因素，环境风险因素和GXE，以及带有和不带有类风湿因子因子抗体（RF？）的RA；和2C：将这种综合风险模型应用于RA病例和控制和通过特定免疫表型分层的RA子集，并根据RA和其他自身免疫性疾病的家族史进行了分层。拟议的研究将利用NIH资助的信息学来整合生物学和床边研究，该研究使用先进的信息学基础设施来通过数据库挖掘和NLP提取RA诊断特征的临床数据。使用高度特定的算法来识别RA病例并从病例和对照中收集样品。 NLP技术将用于从临床注释中提取风险因素数据。该提案建立在我的POR的良好记录上，扩展了从新的病例对照收集中增加家族史的工作，通过患者访谈验证数据，并为RA风险开发了预测模型，可用于为未来的RA预防试验选择高风险个人。