Gene variants and haplotypes in the cytotoxic T-Lymphocyte Antigen 4 (CTLA4)/inducible co-stimulator (ICOS) locus are associated with rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC) in the Canadian population, study findings indicate.
CTLA4 and ICOS are immunoregulatory proteins encoded by adjacent genes (CTLA4 and ICOS) on chromosome 2q33.
Polymorphisms in CTLA4 have previously been implicated in both RA and PBC, but data are inconsistent, and the adjacent gene encoding ICOS, has not been studied extensively, note Katherine Siminovitch (Mount Sinai Hospital, Toronto, Ontario, Canada) and colleagues.
Siminovitch and team therefore examined whether CTLA4 and ICOS influence RA and PBC susceptibility by testing CTLA4/ICOS polymorphisms for association with these diseases in 1140 RA patients, 481 PBC patients, and 1248 healthy controls.
The researchers genotyped all study participants for 21 bi-allelic polymorphisms across the CTLA4/ICOS genes and found multiple significant associations with RA and PBC. The strongest association signals for both diseases were observed for the CTLA4/ICOS intergenic single-nucleotide polymorphism, rs17268364.
Further associations, conferring risk for, or protection from, both diseases were observed with other alleles and haplotypes across three linkage disequilibrium blocks within the CTLA4 gene, the intergenic region, and the ICOS gene.
“While the biologic relevance of such polymorphisms remains unclear, variants in the ICOS intron 1 and 3’ regions appear to regulate messenger RNA levels of CTLA4 and ICOS, respectively, and may thereby modulate expression of these receptors,” write Siminovitch and co-authors in the journal Arthritis and Rheumatism.
The researchers conclude: “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.”
They add that further work is required to dissect a molecular pathway that is “key to the understanding and, ultimately, the treatment of the numerous autoimmune diseases associated with CTLA4/ICOS region polymorphisms.”