CTLA4 is differentially associated with autoimmune diseases in the Dutch population

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type I diabetes (TlD) has recently been demonstrated. The frequent coassociation of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T I D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset TlD and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 TlD, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). TlD patients showed the highest association with the MH30*G: -1147*C: +49*G: CT60*G: JO37 3*G (haplotype 2) in both a case/control cohort (P=0.002, OR = 1.42) and by TDT (P = 0.02, OR = 1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: - 1147*T: + 49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR= 1.6, P = 0.026, P-c = 0.052). Furthermore, when TlD and CD patients were stratified based on the HLA risk, the TlD susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk TlD and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and TlD in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in TlD and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.