description
- Coeliac disease (a common immune condition of the gut caused by reaction to dietary wheat and cereals) runs strongly in families, however at most half of this heritability can be explained by our current knowledge of inherited genetic risk factors. We think that mutations in DNA sequence that alters the protein coding sequence of genes may contribute to coeliac disease heritability. There is evidence for this in other diseases. These risk mutations are likely to be relatively rare in the population. We propose to use new technology to sequence all protein coding genes (the exome) in 50 selected very large multiply affected families with coeliac disease. Each family has at least 5 people with coeliac disease, one has 13 affected individuals. We will study three distantly related individuals per family and look for mutations shared between the people with coeliac disease. This will enable us to narrow down the possibilities from the many thousands of variants the sequencing uncovers. We will also use relatively cheap BeadChips to analyse hundreds of thousands of known variants in every affected individuals in each family. This will give us complementary information, showing which large regions of the genome are shared between the affected individuals. We will subsequently test all individuals (affected and unaffected) in a family for promising candidates for disease causing risk mutations. Once we have found new disease risk mutations in several genes, we will then look for different, possibly rare mutations in thousands of more samples. Finding multiple mutations in a gene gives further evidence that we are on the right track, and also provides information to develop diagnostic and risk-predicting tests. Finally, we will also test several thousand mutations in over ten thousand coeliac and healthy individuals. This will give further evidence to implicate disease mutations, and tell us precise details about each mutation. Identifying rare high effect size mutations in coeliac disease will give us direct leads into how disease develops and possibly identify new targets for treatments. We have previously shown that insights in coeliac disease are likely to give insights relevant to other chronic immune diseases.These rare mutations often have readily predictable consequences, and are of high value for disease understanding. Follow on studies will investigate the effects of these mutations on biological function. The study will likely also generate methodological advances relevant to other conditions.