Novel Biomarkers and Causal Pathways in RA Susceptbility

描述(申请人提供)：类风湿性关节炎，一种不成比例地影响女性的致残性疾病，其发病机制仍不完全清楚。早期诊断和治疗战略对于最大限度地减少联合破坏造成的残疾至关重要。对疾病高危个体的识别可以在患者无症状的临床前阶段进行预防。自身抗原识别异常的过早免疫衰老可能是类风湿关节炎发展的核心。针对瓜氨酸多肽的自身抗体日益被认为是特定的生物标志物，并可能导致严重的、侵蚀性的和遗传性的RA，并且可能是 可检测到的风湿性关节炎前几年。人们开始了解这一自身抗体家族的良好特异性，以及它们与吸烟和类风湿关节炎发病机制的关系。吸烟、早期全身炎症和氧化应激与RA风险相关。其他研究小组的研究表明，端粒缩短在RA受试者中增加，端粒缩短部分由遗传因素决定，部分由衰老、吸烟、全身炎症和氧化应激决定。端粒缩短可能是与RA后续发展相关的潜在生物标志物，但目前尚不清楚端粒在RA发病前是否缩短，也不知道端粒缩短是否与未来RA风险有关。过去关于类风湿关节炎端粒缩短的研究规模较小，采用的是回顾性或横断面设计。他们依赖于与对照组相比，受RA影响的受试者的实验室异常，并不能解决异常是否早于RA的发病。拟议调查的目的是促进对类风湿关节炎病因的了解，并加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的抗瓜氨酸肽自身抗体是否与 女性类风湿性关节炎的未来风险。自1976年以来，护士健康研究的前瞻性队列有超过240,000名参与者，其中包括最大的女性人群，他们拥有在RA发病前几年收集的银行血液样本和详细的暴露数据。这些独特的队列非常适合研究端粒长度和新型瓜氨酸肽抗体作为类风湿关节炎发展的生物标记物。我们将在抽血和RA发病之间的时间间隔内调查端粒长度的临床前异常和新的自身抗体。我们将使用因果路径分析来研究新发现的和复制的端粒长度相关和RA相关的遗传变异、新型抗瓜氨酸肽自身抗体、全身炎症的生物标记物、端粒长度和RA易感性之间的因果关系。端粒缩短在类风湿性关节炎发生发展中的潜在作用是一个新的和尚未回答的问题，这些创新性的研究有望为类风湿性关节炎的发病机制和风险预测提供极其重要的信息。 与公共卫生相关：类风湿性关节炎(RA)是一种致残性自身免疫性疾病，其病因尚不完全清楚。针对特定修饰多肽的抗体最近被发现是严重的、侵蚀性的和遗传性类风湿性关节炎的标志，并且可能比类风湿性关节炎早几年被检测到。端粒是染色体末端的重复序列，随着年龄的增长而缩短，据报道，与健康人相比，RA患者的端粒更短。这些研究的目的是全面检测端粒长度和新型特异性自身抗体与类风湿性关节炎风险的关系，以了解这些标志物是否独立预测类风湿性关节炎或反映其他危险因素，如吸烟或全身炎症。

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. PUBLIC HEALTH RELEVANCE: The cause of rheumatoid arthritis (RA), a disabling autoimmune disease, is incompletely understood. Antibodies to specific modified peptides have recently been found to be markers of severe, erosive, and hereditary RA, and may be detectable years prior to RA. Telomeres, repeated sequences at the ends of chromosomes, shorten with age, and have been reported to be shorter in people with RA compared to healthy individuals. The goal of these studies is to comprehensively examine telomere length and novel specific autoantibodies in relation to RA risk to understand whether these markers independently predict RA or reflect other risk factors, such as smoking or systemic inflammation.