Contribution of the MHC region to the familial risk of coeliac disease

Susceptibility to coeliac disease is genetically determined by possession o f specific HLA-DQ alleles, acting in concert with one or more non-HLA linke d genes. The pattern of risk seen in sibs and twins in coeliac disease is m ost parsimonious with a multiplicative model for the interaction between th e two classes of genes. Based on a sib recurrence risk for coeliac disease of 10% and a population prevalence of 0.0033, the sib relative risk is 30. To evaluate the contribution of the MHC region to the familial risk of coel iac disease, we have examined haplotype sharing probabilities across this r egion in 55 coeliac disease families. Based on these probabilities the sib relative risk of coeliac disease associated with the MHC region is 3.7. Com bining these results with published data on allele sharing at HLA, the esti mated sib relative risk associated with the MHC region is 3.3. Therefore, t he MHC genes contribute no more than 40% of the sib familial risk of coelia c disease and the non-HLA linked gene (or genes) are likely to be the stron ger determinant of coeliac disease susceptibility.