Genome Screening Of Coeliac Disease

Coeliac disease is caused by T cell sensitisation of the intestine to cereal prolamins, which results in a range of mucosal abnormalities that may lead to malabsorption.1 The population prevalence in western countries is ∼1 in 200.2–4 Evidence for an inherited predisposition to coeliac disease comes from studies of first degree relatives of patients and studies of twins.5,6 A strong association is seen between coeliac disease and the HLA-DQ (α1*05, β1*02) heterodimer (DQ2) which is present in approximately 95% of patients,7–9 compared with 20-30% of healthy subjects.10,11 The difference in concordance rates between monozygotic twins and HLA identical sibs (80-100% v 25%) implicates non-HLA genes in the genetic predisposition to coeliac disease.11 The overall relative risk in sibs is at least 20 and is therefore four-fold higher than that attributable to HLA alone under model of inheritance.7 Genome linkage searches carried out on Irish,12 Italian,13, and UK14 coeliac disease families have identified a number of potential sites for the location of non-HLA linked genes. The putative candidate loci detected in the three studies are, however, largely inconsistent and the findings have not been replicated in other populations.15–19 Here we report the results of a genome screen of 24 multiplex families with coeliac disease and discuss the findings of this study in relation to previously published analyses. Twenty-four families with two or more members affected with coeliac disease were recruited for this study (fig 1). Nine of these families (Nos 1, 3, 4, 6, 30, 32, 39, 43, and 44) have been used in a previous study of candidate regions.16 All the families were of northern European ancestry. Twelve of the families were recruited from the UK, nine from Sweden, two from Switzerland, …