Allele specific expression in lymphocyte subsets from patients with multiple sclerosis

多发性硬化症患者淋巴细胞亚群中等位基因的特异性表达

• 批准号: G1100125/1
• 负责人: Stephen Sawcer
• 金额: $ 31.41万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100125%2F1
• 关键词: Allele; specific; expression; lymphocyte; subsets

Multiple sclerosis is the most common cause of neurological disability in young adults. The factors that influence susceptibility and/or govern its highly variable course remain unknown. Over the past three years, several large genome-wide association studies in multiple sclerosis have been completed, providing an unbiased assessment of the factors that influence susceptibility. At present there are 26 known MS genetic markers, and with the recent completion of the largest GWAS in multiple sclerosis of over 10,000 cases, this list will expand considerably. As our knowledge of the genetic factors contributing to disease susceptibility increases, the next priority is to understand the functional consequences of these genetic variants. One such mechanism may be through the regulation of gene expression. We will recruit a large sample of 200 cases and 200 controls and test all common coding variants in genes lying within regions containing established multiple sclerosis susceptibility variants to examine if there is allele specific expression (ASE) in heterozygous samples. By directly examining for the preferential expression of one allele, this provides a measure of the ?real? effect on expression by reducing the effects of environmental and other factors that can influence gene expression. ASE will be analysed in two subpopulations of T cells (CD4+ and CD8+), which are known to be involved in the disease pathology of multiple sclerosis as well as in 64 brain tissue samples. By looking for ASE in both cases and controls we will be able to examine if the spectrum of ASE differs between cases and controls and in examining both T cells and brain tissue we can correlate observed ASE with a particular cell/tissue phenotype.The susceptibility loci thus far established in multiple sclerosis do not account for all the heritability seen epidemiologically, and it is thought that some of this may be explained by parent-of-origin effects. By recruiting and genotyping both parents of the 200 cases for all the variants studied, we will examine for parent-of-origin effects at loci showing ASE and assess whether these parental effects are restricted to specific cell/tissues.This systematic analysis of ASE across the regions identified from our genome screening work will provide greater understanding of the effects of associated genetic variants on gene expression. Understanding the cells/tissues in which these effects are present will also help to refine disease mechanisms and promote the development of logical new therapies.

多发性硬化症是年轻人神经残疾的最常见原因。影响易感性和/或控制其高度可变过程的因素尚不清楚。在过去的三年中，在多发性硬化症中进行了一些全基因组的关联研究，从而对影响易感性的因素进行了公正的评估。目前，有26个已知的MS遗传标记，并且随着最近最大的GWAS在多发性硬化症中最大的10,000例病例完成，此列表将大大扩展。随着我们对导致疾病易感性的遗传因素的了解，下一个优先级是了解这些遗传变异的功能后果。一种这样的机制可能是通过调节基因表达。我们将募集200例和200例对照组的大量样本，并测试包含已建立多发性硬化症易感性变体的区域内的所有常见编码变体，以检查杂合样品中是否存在特定于等位基因的表达（ASE）。通过直接检查一个等位基因的优先表达，这提供了衡量的量度？通过减少可能影响基因表达的环境和其他因素的影响来对表达的影响。 ASE将在T细胞（CD4+和CD8+）的两个亚群中进行分析，这些细胞涉及多发性硬化症以及64个脑组织样品的疾病病理学。通过在两个病例和对照中寻找ASE，我们将能够检查ASE的频谱在病例和对照之间以及在检查T细胞和脑组织时是否可以将ASE与特定细胞/组织表型相关联。该基因在多发性巩膜中无法说明所有的遗传性在流行性上所见，因此在某些遗传性上却被认为是流行性的，并且这是某种效果。通过为所有研究的所有变体招募和基因分型父母，我们将检查ASE的原始父母效应，并评估这些父母的影响是否仅限于特定的细胞/组织。从我们的基因组筛查工作中确定的ASE的系统分析将提供对相关遗传变异表达的影响更大的区域中的ASE。了解存在这些作用的细胞/组织也将有助于完善疾病机制并促进逻辑新疗法的发展。