CTLA4/ICOS Gene Variants and Haplotypes Are Associated With Rheumatoid Arthritis and Primary Biliary Cirrhosis in the Canadian Population

Objective. The co-occurrence of different autoimmune diseases in patients and their families suggests the presence of shared genetic risk factors. Two compelling candidate autoimmune disease susceptibility genes are those that encode CTLA4 and inducible costimulator (ICOS), immunoregulatory proteins. Associations of CTLA4 polymorphisms with various autoimmune diseases have been reported, but for rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC), the association data are inconsistent and have largely excluded analysis of polymorphisms in the ICOS gene adjacent to CTLA4. We undertook this study to examine whether CTLA4 and ICOS influence RA and PBC susceptibility by testing CTLA4/ICOS polymorphisms for association with these diseases in Canadian subjects. Methods. Caucasian RA patients (n = 1,140), PBC patients (n = 481), and controls (n = 1,248) were typed for 21 biallelic polymorphisms across the CTLA4/ICOS genes using a multiplex genotyping array, and the results were analyzed using a false discovery rate method to correct for multiple testing. Results. Significant associations of multiple CTLA4 and ICOS gene polymorphisms with RA and PBC were observed, with the strongest association signals for both diseases coming from a CTLA4/ICOS intergenic single-nucleotide polymorphism, rs17268364 (corrected P [P-corr] = 6.0 x 10(-4) and P-corr < 1.0 x 10(-4), respectively). Significant associations, which were common to both diseases, were also observed with other alleles and haplotypes across 3 linkage disequilibrium blocks within the CTLA4 gene, the intergenic region, and the ICOS gene. Conclusion. Our results provide evidence for RA and PBC association with the CTLA4/ICOS locus and suggest that the risk allele(s) within this region may be common to both diseases.