A L King

A genome-wide family-based linkage study of coeliac disease.

The susceptibility to develop coeliac disease (CD) has a strong genetic component, which is not entirely explained by HLA associations. Two previous genome wide linkage studies have been performed to identify additional loci outside this region. These studies both used a sib‐pair design and produced conflicting results.

CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families

Coeliac disease (CD) is a malabsorption disorder characterised by a small intestinal enteropathy that reverts to normal on removal of dietary gluten. Susceptibility to disease has a strong genetic component. Ninety percent of patients in northern Europe have the HLA class II alleles DQA1*0501 and DQB1*0201, which encode the cell surface molecule HLA-DQ2.1 However, haplotype sharing probabilities across the HLA region in affected sib pairs suggest that genes within the MHC complex contribute no more than 40% of the sib familial risk of CD, making the non-HLA linked gene (or genes) the stronger determinant.2 Attempts have been made to identify these loci using genome wide linkage studies. Zhong et al 3 performed an autosomal screen in 45 affected sib pairs from the west coast of Ireland, using 328 microsatellite markers. They found evidence of linkage with lod scores of greater than 2.0 in five areas: 6p23 (separate from HLA), 7q31.3, 11p11, 15q26, and 22cen. A larger genome wide search involving 110 affected Italian sib pairs using 281 markers found no evidence of linkage in these five areas.4 It did, however, propose a novel susceptibility locus at 5qter, important in both symptomatic and silent CD, and another at 11qter, which appeared to differentiate the two forms. In UK families an initial genome wide search,5 followed by a study of 17 candidate regions6 identified five areas with lod scores of greater than 2.0: 6p12, 11p11, 17q12, 18q23, and 22q13. Of these, 11p11 replicates one of the loci identified by Zhong et al 3 and it is likely that this area contains an important non-HLA susceptibility locus. However, in general the results of these studies are disappointingly inconsistent. A number of candidate genes have been investigated in linkage and association studies. Of these, the only region with repeatedly …

Coeliac disease: follow-up linkage study provides further support for existence of a susceptibility locus on chromosome 11p11

Susceptibility to coeliac disease has a strong genetic component. The HLA associations have been well described but it is clear that other genes outside this region must also be involved in disease development. Two previous genome‐wide linkage studies using the affected sib pair method produced conflicting results. Our own family based linkage study of 16 highly informative pedigrees identified 17 possibly linked regions, each of which produced a result significant at p < 0.05 or less.

Coeliac disease and Down syndrome: associations not due to genetic linkage on chromosome 21.

BACKGROUND Individuals with Down syndrome have an increased prevalence of coeliac disease (CD). The HLA region accounts for only 30% of the heritability of CD, and segregation analyses have suggested the involvement of at least one other non-HLA gene. Distribution of known HLA susceptibility types in Down syndrome and normal populations are similar and do not explain the difference in disease frequency. This study tests the hypothesis that the association between these disorders is due to a susceptibility gene for coeliac disease being present on chromosome 21. METHODS We studied 21 families multiply affected with CD, none of whom had Down syndrome. The typing information of six microsatellite markers across chromosome 21 was used to test linkage. RESULTS Negative results from lod score and model-free linkage analysis were obtained, providing no support for genetic linkage of coeliac disease to chromosome 21 in this population. CONCLUSIONS The high prevalence of coeliac disease in Down syndrome is not due to an increased copy number of a polymorphic susceptibility gene on chromosome 21.