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系统残疾的最常见原因。影响易感性和/或控制其高度可变的过程的因素仍然未知。在过去的三年中，已经完成了几项大型的多发性硬化症全基因组关联研究，为影响易感性的因素提供了无偏见的评估。目前有26个已知的MS遗传标记，随着最近完成的最大的GWAS在多发性硬化症超过10，000例，这个名单将大大扩大。随着我们对导致疾病易感性的遗传因素的了解的增加，下一个优先事项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基因表达的调节。我们将招募200例病例和200例对照的大样本，并测试位于包含已确定的多发性硬化症易感性变体的区域内的基因中的所有共同编码变体，以检查杂合子样本中是否存在等位基因特异性表达（ASE）。通过直接检查一个等位基因的优先表达，这提供了一个衡量？真实的？通过减少环境和其他可能影响基因表达的因素对表达的影响。ASE将在两个T细胞亚群（CD 4+和CD 8+）中进行分析，已知这两个亚群参与多发性硬化症的疾病病理学以及64个脑组织样本。通过在病例和对照中寻找ASE，我们将能够检查ASE谱在病例和对照之间是否不同，并且在检查T细胞和脑组织中，我们可以将观察到的ASE与特定的细胞/组织表型相关联。人们认为，这其中的一些可能是由起源的父母效应来解释的。通过招募和基因分型的200例父母双方的所有研究的变异，我们将检查父母的原产地的影响，在基因座显示ASE和评估这些父母的影响是否仅限于特定的细胞/tissues.This系统的分析ASE跨区域确定从我们的基因组筛选工作将提供更好的理解相关的遗传变异对基因表达的影响。了解存在这些效应的细胞/组织也将有助于完善疾病机制并促进合理的新疗法的开发。