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。在过去的三年里，几项针对多发性硬化症的大型全基因组关联研究已经完成，为影响易感性的因素提供了公正的评估。目前已知的多发性硬化症遗传标记有 26 个，随着近期完成的多发性硬化症最大规模 GWAS（超过 10,000 例），该列表将大幅扩展。随着我们对导致疾病易感性的遗传因素的了解不断增加，下一个优先事项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基因表达的调节。我们将招募 200 个病例和 200 个对照的大样本，并测试包含已确定的多发性硬化症易感性变异的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)。通过直接检查一个等位基因的优先表达，这提供了“真实”的衡量标准。通过减少环境和其他可能影响基因表达的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，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，我们将能够检查病例和对照之间的 ASE 谱是否不同，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/组织表型相关联。迄今为止在多发性硬化症中建立的模型并不能解释流行病学上看到的所有遗传性，并且人们认为其中一些可能可以通过亲本效应来解释。通过招募 200 个病例的所有研究变体的父母并对其进行基因分型，我们将检查显示 ASE 的位点上的亲本效应，并评估这些亲本效应是否仅限于特定细胞/组织。从我们的基因组筛选工作中确定的区域将有助于更好地了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逻辑新疗法的开发。