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Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease

Susceptibility to coeliac disease involves HLA and non‐HLA‐linked genes. The CTLA4/CD28 gene region encodes immune regulatory T‐cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta‐analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non‐parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0·004 and 0·039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0·0001 and 0·0014 at D2S2214, respectively, and 0·0008 and 0·0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.