Novel Biomarkers and Causal Pathways in RA Susceptbility

RA 易感性的新生物标志物和因果途径

• 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
• 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' 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

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）：类风湿性关节炎是一种严重影响女性的致残疾病，其发病机制尚不完全清楚。早期诊断和治疗策略对于减少关节破坏造成的残疾至关重要。在患者无症状的临床前阶段，对疾病高危人群的识别可以导致预防。过早的免疫衰老和对自身抗原的异常识别可能是RA发展的核心。瓜氨酸化肽的自身抗体越来越被认为是一种特殊的生物标志物，并且可能是严重的、侵蚀性的和遗传性RA的潜在因素