Allele specific expression in lymphocyte subsets from patients with multiple sclerosis

多发性硬化症是年轻人神经功能障碍的最常见原因。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，对影响易感性的因素进行了公正的评估。目前已知的多发性硬化症遗传标记有26个，随着最近在超过1万例多发性硬化症中最大的GWAS的完成，这一列表将大大扩大。随着我们对导致疾病易感性的遗传因素的了解的增加，下一个重点是了解这些遗传变异的功能后果。其中一种机制可能是通过调控基因表达。我们将招募200例病例和200例对照的大样本，并测试包含已建立的多发性硬化症易感性变异区域内基因的所有常见编码变异，以检查杂合样本中是否存在等位基因特异性表达（ASE）。通过直接检测一个等位基因的优先表达，这提供了一种“真实”的衡量标准。通过减少影响基因表达的环境和其他因素的影响来影响表达。ASE将在两个T细胞亚群（CD4+和CD8+）中进行分析，这两个亚群已知参与多发性硬化症的疾病病理以及64个脑组织样本。通过在病例和对照组中寻找ASE，我们将能够检查ASE的谱在病例和对照组之间是否不同，并且在检查T细胞和脑组织时，我们可以将观察到的ASE与特定的细胞/组织表型联系起来。到目前为止，多发性硬化症的易感性位点并不能解释流行病学上看到的所有遗传性，有人认为，其中一些可能是由父母的起源效应来解释的。通过招募和分型研究的所有变异的200个病例的双亲，我们将在显示ASE的位点检查亲本起源效应，并评估这些亲本效应是否局限于特定的细胞/组织。从我们的基因组筛选工作中确定的跨区域的ASE系统分析将更好地理解相关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乎逻辑的新疗法的发展。

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.