CTLA-4 +49 A/G dimorphism in Italian patients with celiac disease.

The chromosome region 2q33, which contains the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, has been reported in linkage and association with celiac disease (CD). In the present work we have tested the association between the polymorphism of the CTLA-4 exon 1 and susceptibility to CD in an Italian population, using case-control and family-based approaches. The +49 A/G dimorphism was analyzed in 86 patients, 144 ethnically matched controls, and 113 nuclear families by the polymerase chain reaction-restriction fragment length polymorphism method. A significantly higher frequency of the CTLA-4 +49A allele was observed in patients when compared with controls (p = 3 x 10(-2)). The segregation analysis in the 113 trios showed a preferential transmission of the A allele to the probands (chi(2)(TDT) = 4.85). When the patients were stratified according to the presence/absence of the high-risk human leukocyte antigen-DQ2 heterodimer, a significant difference was observed between the two groups, that is, the A allele was increased in the subjects without the DQ2 heterodimer (88.9% vs 73.5%, p = 8.3 x 10(-3)). The A allele was transmitted from heterozygous parents to eight of nine DQ2-dimer-negative patients. These data support CTLA-4 as a predisposing gene for CD in an Italian population with a prominent role in patients not carrying the high-risk human leukocyte antigen-DQ2 molecules.