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CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families
  1. A L King1,
  2. S J Moodie1,
  3. J S Fraser1,
  4. D Curtis2,
  5. E Reid3,
  6. A M Dearlove4,
  7. H J Ellis1,
  8. P J Ciclitira1
  1. 1Gastroenterology Unit, GKT, The Rayne Institute, St Thomas's Hospital, London SE1 7EH, UK
  2. 2Academic Department of Psychological Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, 3rd Floor Alexandra Wing, Turner Street, London E1, UK
  3. 3Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
  4. 4UK HGMP Resource Centre, Hinxton, Cambridge CB10 1SB, UK
  1. Correspondence to:
 Professor P J Ciclitira, Department of Gastroenterology (GKT), The Rayne Institute, St Thomas's Hospital, London SE1 7EH, UK;

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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 al3 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 al3 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 …

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