Novel Biomarkers and Causal Pathways in RA Susceptbility

RA 易感性的新生物标志物和因果途径

基本信息

批准号：
8457143
负责人：
Karen H Costenbader
金额：
$ 36.63万
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：
2010
资助国家：
美国
起止时间：
2010-04-09 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457143
关键词：
Address Affect Age Aging Alleles Antibodies Archives Arthritis Autoantibodies Autoantigens Autoimmune Diseases B-Cell Activation Biological Assay Biological Markers Blood Blood specimen Cartilage Cells Chromosomes Chronic Citrulline Cohort Studies Collagen Type II Data Deltastab Detection Development Disease Distal Early Diagnosis Early treatment Environmental Risk Factor Etiology Family Fibrinogen Future Genes Genetic Genetic Determinism Genome Goals HLA Antigens Hematopoietic stem cells Individual Infiltration Inflammation Inflammatory Inherited Investigation Joints Laboratories Lead Length Leukocytes Molecular Nurses&apos Health Study Oxidative Stress PTPN22 gene Participant Pathogenesis Pathway Analysis Pathway interactions Patients Peptide Hydrolases Peptide antibodies Peptides Phenotype Population Predisposition Prevention Reporting Research Personnel Rheumatoid Arthritis Risk Risk Factors Role Smoking Specificity Synovial Membrane T-Cell Activation Techniques Telomere Shortening Vimentin Woman Work age related cancer epidemiology cigarette smoking cohort cost effective cytokine design disability disabling disease disease diagnosis enolase follow-up genetic risk factor genetic variant genome wide association study high risk immunosenescence innovation interest joint destruction macrophage monocyte novel peripheral blood pre-clinical premature prevent prospective public health relevance systemic autoimmune disease telomere time interval treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The pathogenesis of RA, a disabling disease that disproportionately affects women, remains incompletely understood. Early diagnosis and treatment strategies are critical to minimize disability from joint destruction. The identification of individuals at high risk for disease could lead to prevention during the pre-clinical period when patients are asymptomatic. Premature immunosenescence with aberrant recognition of self-antigens may be central to RA development. Autoantibodies to citrullinated peptides are increasingly recognized as specific biomarkers, and potentially contributing agents of severe, erosive, and hereditary RA, and may be detectable years prior to RA. The fine specificity of this family of autoantibodies is beginning to be understood, as is their relationship to smoking and systemic inflammation in RA pathogenesis. Smoking, early systemic inflammation and oxidative stress are related to RA risk. Work by other groups has shown that telomere shortening, determined in part by genetic factors and in part by aging, smoking, systemic inflammation and oxidative stress, is increased in RA subjects. Telomere shortening could be a potential biomarker associated with subsequent RA development, but it is not known whether telomeres are shortened prior to RA onset, nor whether this shortening is related to future RA risk. Past studies examining telomere shortening in RA have been small, with retrospective or cross-sectional designs. They have relied upon laboratory abnormalities in subjects affected with RA compared to controls and could not address whether abnormalities predate RA onset. The goals of the proposed investigations are to advance understanding of RA etiology and to enhance prediction of this serious disease. These investigations are designed to address the important questions of whether telomere shortening and specific new anti-citrullinated peptide autoantibodies are associated with future risk of RA in women. The Nurses' Health Study prospective cohorts with over 240,000 participants followed since 1976 contain the largest population of women with banked blood samples and detailed exposure data collected years prior to RA onset. These unique cohorts lend themselves perfectly to the investigation of telomere length and novel citrullinated peptide antibodies as biomarkers for RA development. We will investigate preclinical abnormalities in telomere length and novel autoantibodies within time intervals between blood draw and RA onset. We will employ causal pathway analyses to investigate causal relationships between newly identified and replicated telomere length-associated and RA-associated genetic variants, novel anti-citrullinated peptide autoantibodies, biomarkers of systemic inflammation, telomere length and RA susceptibility. The potential role of telomere shortening in the development of RA is a novel and unanswered question and these innovative studies promise to furnish extremely important information about RA pathogenesis and risk prediction.

描述（由申请人提供）：RA的发病机理，一种致命的疾病，对女性的影响不成比例，但仍未完全理解。早期诊断和治疗策略对于最大程度地减少关节破坏的残疾至关重要。在患者无症状的临床前时期，鉴定出高风险的个体可能会导致预防。对自我抗原的异常识别的过早免疫衰老可能是RA发育的核心。瓜氨酸肽的自身抗体越来越被认为是特定的生物标志物，并可能造成严重，侵蚀性和遗传性RA的毒剂，并且可能是 RA前可检测的几年。这种自身抗体家族的良好特异性开始被理解，就像它们在RA发病机理中与吸烟和全身炎症的关系。吸烟，早期全身炎症和氧化应激与RA风险有关。其他群体的工作表明，在RA受试者中，端粒缩短部分取决于遗传因素，部分由衰老，吸烟，全身炎症和氧化应激确定。端粒缩短可能是与随后的RA开发相关的潜在生物标志物，但尚不清楚端粒是否在RA发作之前缩短，也不知道这种缩短是否与未来的RA风险有关。过去检查RA中端粒缩短的研究很小，具有回顾性或横截面设计。与对照组相比，他们依靠RA影响的受试者的实验室异常，无法解决是否早于RA发作。拟议的调查的目标是提高对RA病因的理解，并增强对这种严重疾病的预测。这些研究旨在解决端粒缩短和特定的新抗抗硝化肽自身抗体是否与之相关的重要问题女性RA的未来风险。自1976年以来，护士健康研究的前瞻性人群与240,000名参与者有关，其中包含最大的有储存血液样本的妇女人群，以及在RA发作之前收集的几年收集的详细接触数据。这些独特的人群非常适合将端粒长度和新型瓜氨酸肽抗体作为RA发育的生物标志物的研究。我们将在血液抽水和RA发作之间的时间间隔内研究端粒长度和新型自身抗体的临床前异常。我们将采用因果途径分析来研究新鉴定的和复制的端粒长度相关和与RA相关的遗传变异，新型抗抑制肽自身抗体，全身性炎症，端粒长度和RA易感性之间的因果关系。端粒缩短在RA发展中的潜在作用是一个新颖且未解决的问题，这些创新的研究有望提供有关RA发病机理和风险预测的极为重要的信息。