Novel Biomarkers and Causal Pathways in RA Susceptbility

描述（由申请人提供）：RA是一种致残性疾病，不成比例地影响女性，其发病机制仍不完全清楚。早期诊断和治疗策略对于尽量减少关节破坏造成的残疾至关重要。确定疾病高风险个体可导致在患者无症状的临床前阶段进行预防。过早的免疫衰老与自身抗原的异常识别可能是RA发展的核心。瓜氨酸化肽自身抗体越来越被认为是特异性生物标志物，并且是严重的、侵蚀性的和遗传性RA的潜在促成因素，并且可能是 在RA之前几年就可以检测到。这个家族的自身抗体的精细特异性开始被理解，因为它们与吸烟和RA发病机制中的全身炎症的关系。吸烟、早期全身炎症和氧化应激与RA风险相关。其他研究小组的工作表明，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，在RA受试者中增加。端粒缩短可能是与随后的RA发展相关的潜在生物标志物，但尚不清楚端粒是否在RA发作前缩短，也不知道这种缩短是否与未来的RA风险有关。过去研究RA端粒缩短的研究较少，采用回顾性或横断面设计。他们依赖于RA受试者与对照组相比的实验室异常，无法解决异常是否早于RA发作。建议调查的目标是提高对RA病因的认识，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异性新的抗瓜氨酸肽自身抗体是否与 女性未来患RA的风险。自1976年以来，护士健康研究前瞻性队列有超过240，000名参与者，其中包含最大的女性人群，在RA发作前几年收集了库存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RA发展的生物标志物。我们将研究临床前异常端粒长度和新的自身抗体之间的时间间隔抽血和类风湿关节炎发作。我们将采用因果通路分析来研究新发现和复制的端粒长度相关和RA相关遗传变异、新型抗瓜氨酸肽自身抗体、全身性炎症生物标志物、端粒长度和RA易感性之间的因果关系。端粒缩短在类风湿关节炎发病中的潜在作用是一个新的和未回答的问题，这些创新的研究有望提供关于类风湿关节炎发病机制和风险预测的极其重要的信息。

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.