The Identification of Risk Factors for the Complex MS Phenotype

复杂 MS 表型危险因素的识别

• 批准号: 7586842
• 负责人: LISA F BARCELLOS
• 金额: $ 76.24万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586842
• 关键词: Affect; Alleles; Arts; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biology; CTLA4 gene; California; Candidate Disease Gene; Central Nervous System Diseases; Clinical; Collection; Complex; Country; Data; Data Set; Databases; Development; Diagnosis; Disease; Disease susceptibility; Educational process of instructing; Electronics; Emotional; Environmental Exposure; Environmental Risk Factor; Etiology; European; Family history of; Family member; Future; Genes; Genetic; Genomics; Genotype; Gliosis; Goals; Haplotypes; Healthcare Systems; Heterogeneity; Individual; Inflammatory; Interview; Major Histocompatibility Complex; Methodology; Multiple Sclerosis; Myelin; Neuraxis; Neurologic; Neurologic Dysfunctions; Outcome; PTPN22 gene; Pathogenesis; Pathology; Patients; Phenotype; Physicians; Play; Predisposition; Productivity; Public Health; Quality of life; Recording of previous events; Research; Resources; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Staging; Subgroup; Surveys; Techniques; Testing; Therapeutic; Time; Unemployment; Universities; analytical tool; base; case control; clinical phenotype; data mining; disability; disease phenotype; disorder prevention; disorder risk; forest; gene environment interaction; genetic risk factor; genome wide association study; non-genetic; novel; novel strategies; population based; social; tool

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. MS is the most common cause of acquired neurological disability in the U.S. and European countries arising during early and mid-adulthood, and it affects more than one million people worldwide. The goal of this proposal is to identify genetic factors and complex interactions between genetic and non- genetic risk factors that predispose to MS and related phenotypes. We describe for the very first time in MS, a powerful and novel approach to pursue well-defined hypotheses based on strong preliminary data that are critical to furthering our understanding of disease pathogenesis. A major focus of this proposal will be the identification of complex risk factors that (a) predispose to the autoimmune prone MS phenotype, and (2) distinguish between MS subgroups defined by the presence or absence of the well-established disease associated HLA-DRB1*15 genotype and other environmental exposures, and (c) the application of novel and powerful analytical tools to identify complex relationships, including interactions, between large numbers of potential risk factors that can predict disease status or related phenotypes. We will study a large, well characterized population-based MS case- control data set comprised of 2,400 individuals. We will use well-established strict ascertainment criteria for MS cases and a suite of sophisticated tools including electronic database surveying, direct physician contact, chart review and comprehensive interviews to determine definite MS diagnoses and important phenotypic designations for this study. State of the art high-throughput genotyping of more than 550,000 informative single nucleotide polymorphisms will be performed. The complete elucidation of genetic and non- genetic influences underlying disease risk and heterogeneous MS phenotypes would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics. PROJECT NARRATIVE Multiple sclerosis (MS) represents a physical, emotional, social and fiscal burden to the health care system and like other autoimmune disorders is a significant public health concern resulting in lost productivity and decreased quality of life. Fifteen years after diagnosis, less than 20% of patients have no functional limitations; 50-60% require ambulating assistance, at least 70% are unable to perform normal daily activities, and 75% are unemployed. The complete elucidation of genetic and non-genetic influences underlying MS would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics.

描述(申请人提供)：多发性硬化症(MS)是一种复杂和异质性的中枢神经系统(CNS)炎症性疾病，以髓鞘丢失、胶质增生、不同程度的轴突病理和进行性神经功能障碍为特征。多发性硬化症是美国和欧洲国家后天神经功能障碍的最常见原因，出现在成年早期和中期，全球有100多万人受到影响。这项建议的目标是确定易患多发性硬化症和相关表型的遗传因素和遗传和非遗传风险因素之间的复杂相互作用。我们首次在MS中描述了一种强大而新颖的方法来追求基于强大的初步数据的明确假设，这些数据对于进一步了解疾病的发病机制至关重要。这项建议的一个主要焦点将是识别复杂的风险因素，这些因素(A)易患自身免疫易感的MS表型，(2)区分由已建立的与疾病相关的HLA-DRB1*15基因型的存在或不存在以及其他环境暴露所定义的MS亚组，以及(C)应用新颖和强大的分析工具来识别复杂的关系，包括可以预测疾病状态或相关表型的大量潜在风险因素之间的相互作用。我们将研究一个由2400名个体组成的大型、特征良好的基于人群的多发性硬化症病例对照数据集。我们将使用完善的MS病例确定标准和一套复杂的工具，包括电子数据库调查、医生直接接触、病历回顾和全面访谈，以确定明确的MS诊断和本研究的重要表型指定。将对550,000多个信息性单核苷酸多态进行高通量高通量基因分型。彻底阐明遗传和非遗传因素对疾病风险的潜在影响以及多发性硬化症的异质性表型显然将在理解疾病生物学方面发挥重要作用，并将对疾病预防和开发有针对性的更有效的治疗方法做出重大贡献。项目叙事 多发性硬化症(MS)是医疗保健系统的身体、情感、社会和财政负担，与其他自身免疫性疾病一样，是一个重大的公共卫生问题，导致生产力下降和生活质量下降。确诊15年后，只有不到20%的患者没有功能障碍；50%-60%的患者需要步行辅助，至少70%的患者无法进行正常的日常活动，75%的患者失业。彻底阐明遗传和非遗传因素对多发性硬化症的潜在影响显然将在理解疾病生物学方面发挥重要作用，并将对疾病预防和开发更有针对性和更有效的治疗方法做出重大贡献。