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

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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.