The genetic basis of progression in multiple sclerosis

多发性硬化症进展的遗传基础

基本信息

批准号：
10084323
负责人：
SERGIO E BARANZINI
金额：
$ 44.28万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084323
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 Prognosis 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 patient population prognostic programs screening success

项目摘要

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.

该提议将寻求识别和表征调节疾病活动和的遗传因素多发性硬化症（MS）的进展。该项目以这样的假设为基础疾病轨迹通过足够动力的无偏基遗传筛查可以明显地识别，并将因此，采用多维统计分析来识别关键基因网络和生物学过程潜在的疾病进展。为了最大程度地减少暂时波动的混杂影响由MS早期阶段的复发性炎症活动引起的残疾该项目的发现阶段将仅关注长期疾病的老年受试者（至少55岁）持续时间（> 10年）。由于通常少于7名患者满足这些标准，因此这种方法仅是由于国际多发性硬化症可用的巨大生物特异性资源，可能遗传联盟（IMSGC）（> 62,000例）。我们将使用多发性硬化症严重程度评分（MSSS）作为我们的进展度量；序数分数分数，指示患者的残疾状况扩大比例（EDSS）与其他具有相同疾病持续时间的患者相比排名。 IMSGC具有DNA 从近9,000名年长的长期疾病持续时间患者中，至少有一项MSS测量。最大效率我们将与我们的同事合作筛选这9,000个案件的案件瑞典。复制结果将立即在细胞特异性途径和TOP的背景下进行分析随后将探讨候选人的遗传相互作用，包括其功能验证。具体而言，在AIM 1中，我们将使用最新一代基因分型对4,000名患者进行GWAS 芯片通过归类将使我们能够评估超过7,000万种变体。在特定目标2中，我们将然后在其余5,000个样本中复制AIM 1中确定的最相关的标记，行为在至少两个独立样本人群中进行额外复制，一项荟萃分析，并执行最有希望的关联的生物信息学和实验验证。将数据结合在一起努力将提供能力，以确定占MSS方差的0.5％的变体。这鉴定疾病表达的遗传修饰符将对了解和管理MS，尤其是渐进式MS，是最残疾，目前最禁用的疾病的不可治疗形式。