FINE MAPPING OF REGULATORY GENETIC VARIATION INVOLVING COMMON AUTOIMMUNE DISEASE ASSOCIATED HAPLOTYPES IN THE HUMAN MHC

自身免疫性疾病，如I型糖尿病、多发性硬化症和克罗恩？S病，涉及到身体通过免疫系统攻击自己。这类疾病很常见，特别是在年轻人中，对他们来说，后果可能是毁灭性的。我们知道，自身免疫性疾病在特定的家庭中更常见，最近的研究表明，许多不同的基因参与其中。特别是，科学家们发现，人类基因组中被称为6号染色体上主要组织相容性复合体的区域，在决定自身免疫性疾病的遗传易感性方面至关重要。我们知道，我们基因组的这一部分包含许多与免疫反应有关的基因。MHC也是基因组中一个非常可变的部分。事实证明，很难定义与MHC内疾病的发生相关的特定遗传变异，或者这些变异如何导致疾病。在这个研究项目中，我们建议调查与疾病相关的基因变异如何影响基因的表达方式。基因是生命的蓝图，它提供了一种代码，通过一种名为RNA的中间分子合成蛋白质。我们将研究RNA是如何从DNA中产生的。我们将在血液中的细胞中进行这项工作，这些细胞在免疫反应中非常重要。我们将研究具有不同遗传背景的健康志愿者，看看这是如何影响基因表达过程的。特别是，我们将研究具有与自身免疫性疾病相关的遗传背景的人。我们还将测量DNA本身中称为甲基化的化学变化，这可能会影响基因的表达方式。DNA甲基化是机体在特定时间调节特定基因在特定细胞中表达的重要控制机制。我们知道，在疾病中，这一过程可能会变得失调，我们计划对参与自身免疫的MHC中的基因进行研究。总体而言，我们的研究将帮助科学家更好地了解人与人之间的基因差异如何控制我们的基因调控方式，并确定我们患自身免疫性疾病的风险。这应该有助于医生找到治疗这些非常重要的疾病的新方法，并将治疗目标对准那些将受益最大的人。这项工作将在牛津大学进行。我们的研究将发表在科学期刊上，并通过在学校、地方和国家媒体上的演讲以及在大学网站上提供信息向公众宣传。

Autoimmune diseases such as type I diabetes, multiple sclerosis and Crohn?s disease involve the body attacking itself through the immune system. Such diseases are common, particularly among younger people, for whom the consequences can be devastating. We know that autoimmune diseases occur more commonly in particular families and recent research has shown that many different genes are involved. In particular, scientists have found that a region of the human genome called the major histocompatibility complex on chromosome 6 is critically important in determining genetic susceptibility to autoimmune disease. We know that this part of our genome contains many genes involved in the immune response. The MHC is also a remarkably variable portion of the genome. It has proved very hard to define the particular genetic variants that are associated with developing disease within the MHC, or how such variants act to cause disease. In this research project we propose to investigate how genetic variation associated with disease affects the way genes are expressed. Genes are the blueprint of life, providing a code from which proteins are synthesized via an intermediary molecule called RNA. We will study how RNA is produced from DNA. We will do this in cells from the blood which are important in the immune response. We will study healthy volunteers who have different genetic backgrounds to see how this affects the process of gene expression. In particular we will study people with genetic backgrounds associated with autoimmune disease. We will also measure chemical changes in the DNA itself called methylation which can affect how genes are expressed. DNA methylation is an important control mechanism for the body to regulate expression of particular genes in particular cells at particular times. We know that this process may become dysregulated in disease and we plan to investigate this for genes in the MHC involved in autoimmunity. Overall our research will help scientists to better understand how genetic differences between people control the way our genes are regulated and define our risk of developing autoimmune diseases. This should help doctors to find new ways of treating these very important diseases and to target therapies to those who will benefit most. The work will be carried out at the University of Oxford. Our research will be published in scientific journals and promoted to the public through presentations at schools, the local and national media, and by providing information on the University website.