The genetic basis of progression in multiple sclerosis

多发性硬化症进展的遗传基础

• 批准号: 9737736
• 负责人: SERGIO E BARANZINI
• 金额: $ 44.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9737736
• 关键词: Accounting; Address; Affect; Age; Benign; Bioinformatics; Biological Assay; Biological Process; Cells; Central Nervous System Diseases; Clinical; Collaborations; Country; DNA; Data; Data Set; Development; Disease; Disease Progression; Face; Future; Generations; Genes; Genetic; Genetic Determinism; Genetic Screening; Genotype; Goals; In Vitro; Individual; Inflammatory; Institutes; International; Joints; Masks; Measures; Meta-Analysis; Multiple Sclerosis; Nerve Degeneration; Nervous System Physiology; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phase; Play; Population; Probability; Relapse; Research; Resources; Running; Sampling; Severities; Statistical Data Interpretation; Subgroup; Sweden; System; Therapeutic; Tissues; Validation; Variant; aged; bioinformatics pipeline; cell type; cohort; cost effective; design; disability; genetic information; genetic variant; genome wide association study; genome-wide; illness length; in silico; individual patient; innovation; insight; interest; multiple sclerosis patient; outcome forecast; patient population; prognostic; programs; screening; success

This proposal will seek to identify and characterize the genetic factors that modulate disease activity and progression in multiple sclerosis (MS). The project builds on the hypothesis that allelic variants affecting disease trajectory are eminently identifiable through adequately powered unbiased genetic screens, and will thus employ a multi-dimensional statistical analysis to identify key gene networks and biological processes underlying disease progression. In order to minimize the confounding influence of the temporary fluctuations in disability that result from the relapsing inflammatory activity that characterizes the early stages of MS the discovery phase of this project will focus exclusively on older subjects (aged at least 55) with a long disease duration (>10 years). Since typically less than 1 in 7 patients satisfy these criteria this approach is only possible because of the enormous bio-specimen resource available to the International Multiple Sclerosis Genetics Consortium (IMSGC) (>62,000 cases). We will use the Multiple Sclerosis Severity Score (MSSS) as our measure of progression; an ordinal decile score that indicates how a patient's Expanded Disability Status Scale (EDSS) ranks in comparison with other patients with the same duration of disease. The IMSGC has DNA from almost 9,000 older long disease duration patients that have at least one MSSS measure. For maximal efficiency we will screen these 9,000 cases in collaboration with our colleagues from the Karolinska Institute in Sweden. Replicated results will be immediately analyzed in the context of cell-specific pathways and top candidates will be subsequently explored for genetic interactions, including their functional validation. Specifically, in Aim 1 we will conduct a GWAS on 4,000 patients using the latest generation of genotyping chips, which through imputation will allow us to assess more than 70 million variants. In Specific Aim 2 we will then replicate the most associated markers identified in aim 1 in the remaining 5,000 samples, conduct additional replications in at least two more independent sample populations, a meta-analysis, and perform bioinformatics and experimental validation of the most promising associations. Combining the data across both efforts will provide power to identify variants accounting for as little as 0.5% of variances in MSSS. The identification of genetic modifiers of disease expression will have profound translational implications for the understanding and management of MS, and in particular for progressive MS, the most disabling and currently untreatable form of the disease.

该提案将寻求确定和描述调节疾病活动的遗传因素， 多发性硬化症（MS）的进展。该项目建立在等位基因变异影响 疾病的轨迹是非常明确的识别，通过足够有力的无偏见的遗传筛选， 从而采用多维统计分析来识别关键基因网络和生物过程 基础疾病进展。为了尽量减少临时波动的混杂影响， 由于MS早期阶段特征性的复发性炎症活动而导致的残疾， 该项目的发现阶段将专门关注患有长期疾病的老年受试者（至少55岁） 持续时间（>10年）。由于通常只有不到七分之一的患者满足这些标准，因此这种方法只是 这是因为国际多发性硬化症组织拥有大量的生物标本资源， 遗传学联合会（IMSGC）（> 62 000例）。我们将使用多发性硬化严重程度评分（MSSS）作为 我们的进展指标;一个有序的十分位数分数，表明患者的扩展残疾状态 量表（EDSS）与其他具有相同病程的患者相比进行排名。IMSGC有DNA 来自近9,000名至少有一项MSSS指标的老年长期疾病患者。用于最大 为了提高效率，我们将与卡罗林斯卡医学院的同事合作， 瑞典.重复的结果将立即在细胞特异性途径的背景下进行分析， 随后将探讨候选基因的相互作用，包括其功能验证。 具体来说，在目标1中，我们将使用最新一代基因分型技术对4，000名患者进行GWAS。 芯片，通过估算，它将使我们能够评估超过7000万个变体。具体目标2 然后在剩下的5,000个样本中复制目标1中确定的最相关的标记， 在至少两个更独立的样本群体中进行额外的重复，进行荟萃分析，并进行 生物信息学和实验验证最有前途的协会。将两者的数据结合起来 这些努力将提供识别变异的能力，变异仅占MSSS变异的0.5%。的 疾病表达的遗传修饰物的鉴定将对疾病的发生和发展具有深远的翻译意义。 理解和管理MS，特别是对于进行性MS，最禁用和目前 无法治愈的疾病。