The Disablement Process in Rheumatoid Arthritis

类风湿关节炎的致残过程

基本信息

批准号：
7900518
负责人：
AGUSTIN ESCALANTE
金额：
$ 57万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900518
关键词：
Address Affect American Candidate Disease Gene Cessation of life Characteristics Clinical Comorbidity Deformity Disease Disease Outcome Disease Pathway Environment Environmental Risk Factor Ethnic Origin Ethnic group Evaluation Event Foundations Funding Genes Genetic Genetic Variation Genotype Goals Grant Impairment Inflammation Intervention Joints Left Longevity Maps Measures Medical Mexican Americans Modeling Motion Names National Institute of Child Health and Human Development Not Hispanic or Latino Nucleotides Operative Surgical Procedures Outcome Pain Pathology Pathology processes Pathway interactions Patients Pattern Performance Pharmaceutical Preparations Phenotype Predisposition Principal Investigator Process Psychosocial Factor Publications Recruitment Activity Research Research Subjects Resources Rheumatoid Arthritis Right-On Risk Role Sample Size Severities Single Nucleotide Polymorphism Social Class Socioeconomic Status Staging Stratification Testing Variant Wood material biopsychosocial bone metabolism cartilage metabolism cigarette smoking cohort disability experience gene function joint injury member novel prevent psychosocial theories trait

项目摘要

DESCRIPTION (provided by applicant): Inflammation damages the joints of rheumatoid arthritis (RA) patients. They experience pain, loss of motion, physical disability and a shortened lifespan. Despite estimates suggesting Mexican Americans (MA) may be more susceptible to RA than other major U.S. ethnic groups, little is known about the clinical expression or outcome in RA in MA. Our goals are to identify optimal points for intervention to retard disablement in RA, and to understand the mechanisms of ethnic disparities. Toward these goals, we developed a novel biopsychosocial model of disability in RA, which guided our study of a multiethnic cohort of 779 RA patients. During the initial funding period from 1999 to 2005, we followed the cohort for 3,967 patient-years. Key findings from the initial period that we aim to study further include: First, a significant ethnic disparity in the clinical expression of RA, MA having more severe manifestations at every stage of the disablement process; and second, extreme variation among the patients in the accrual of joint damage. Our Specific Aims are: 1) To identify gene variants (single nucleotide polymorphisms, or SNPs), associated with the joint damage phenotype in RA, and to examine their downstream influence on the disablement process; 2) To examine the extent to which ethnic variation in the disablement process in RA is explained by genetic and environmental factors; and 3) To examine the influence of ethnicity, genetic and environmental factors on survival in RA. We will study MA and non-Hispanic White (NHW) members of the original RA cohort (n=655) and will recruit additional patients for a combined sample size of 500 MA and 500 NHW RA patients. We will follow patients longitudinally to evaluate the process of disablement, and survival. We will study 25 carefully selected candidate genes found previously to be associated with RA susceptibility and/or severity. In each gene, we will genotype an average of 20 SNPs, selected to capture the largest amount of regional genetic information, or for their potential to alter gene function. We will use Bayesian Quantitative Trait Nucleotide analysis (BQTN) to identify SNPs associated with joint damage. This research will advance current understanding of the genotype-phenotype relationship in RA, and of how genes and the environment contribute to ethnic disparities in the disablement process. SNPs associated with RA damage may be useful for risk stratification of patients, and may contribute to the discovery of novel targets for RA treatments.

描述（由申请人提供）：炎症会损害类风湿性关节炎（RA）患者的关节。他们会经历疼痛、行动不便、身体残疾和寿命缩短。尽管估计表明墨西哥裔美国人 (MA) 可能比美国其他主要种族群体更容易患 RA，但人们对 MA 中 RA 的临床表现或结果知之甚少。我们的目标是确定干预措施的最佳点，以延缓 RA 致残，并了解种族差异的机制。为了实现这些目标，我们开发了一种新的 RA 残疾生物心理社会模型，该模型指导了我们对 779 名 RA 患者的多种族队列的研究。在 1999 年至 2005 年的初始资助期间，我们对队列进行了 3,967 个患者年的跟踪。我们打算进一步研究的初始阶段的主要发现包括：首先，RA、MA 的临床表达存在显着的种族差异，在致残过程的每个阶段都有更严重的表现；其次，患者之间关节损伤的严重程度存在巨大差异。我们的具体目标是： 1) 鉴定与 RA 关节损伤表型相关的基因变异（单核苷酸多态性或 SNP），并检查其对致残过程的下游影响； 2) 研究遗传和环境因素在多大程度上解释了 RA 致残过程中的种族差异； 3) 研究种族、遗传和环境因素对 RA 生存的影响。我们将研究原始 RA 队列 (n=655) 中的 MA 和非西班牙裔白人 (NHW) 成员，并将招募更多患者，合并样本量为 500 名 MA 和 500 名 NHW RA 患者。我们将纵向跟踪患者以评估残疾过程和生存情况。我们将研究 25 个精心挑选的候选基因，这些基因先前被发现与 RA 易感性和/或严重程度相关。在每个基因中，我们将平均对 20 个 SNP 进行基因分型，选择这些 SNP 是为了捕获最大量的区域遗传信息，或者它们改变基因功能的潜力。我们将使用贝叶斯定量特征核苷酸分析 (BQTN) 来识别与关节损伤相关的 SNP。这项研究将增进目前对 RA 基因型与表型关系的理解，以及基因和环境如何导致残疾过程中的种族差异。与 RA 损伤相关的 SNP 可能有助于患者的风险分层，并可能有助于发现 RA 治疗的新靶点。