OR32 Potential role of loci in linkage disequilibrium with DRB1 in the pathogenesis of rheumatoid arthritis

Abstract

Aim Several polymorphic amino acids within the peptide-binding groove of the DR β 1 correlate with rheumatoid arthritis (RA) disease susceptibility and resistance. However, this genetic association accounts for only 60% of RA patients. We have previously demonstrated that susceptible RA alleles prefer binding citrullinated peptides, whereas resistant alleles prefer binding unmodified peptides. On the basis of the shared amino acid sequences in DRB1, several alleles ought to be equivalently susceptible (DRB1∗04:01 and DRB1∗01:01. However, DRB1∗04:01 is significantly more susceptible than DRB1∗01:01. DRB1∗04:01 is in tight linkage disequilibrium with DRB4∗01:01, but DRB1∗01:01 does not possess this linkage. The goal of this study is to examine the possible contribution of DRB4∗01:01 and other cis elements in the development of RA. Methods We measured binding of native and citrullinated forms of vimentin 66–78 ), α -enolase 11–25 and non-citrullinated type II collagen 259–273 , to alleles at loci in linkage disequilibrium with DRB1: DRB3, DRB4, and DRB5. Utilizing tetramers complexed with citrullinated vimentin peptide, we measured the number of T cells restricted to DRB1∗04:01 and DRB4∗01:01 specific for citrullinated vimentin in healthy subjects. Results DRB4∗01:01 exhibited a preference for binding citrullinated peptides over native. Other alleles in linkage disequilibrium with DRB1 exhibited no preference for citrullinated peptides. We observed significant expansion of T cells responding to citrullinated vimentin on DRB4∗01:01 Conclusions These observations suggest that the DRB4 locus may contribute to RA susceptibility and help to explain the differences in susceptibility among shared epitope alleles through a gene dose effect: expressing alleles DRB1∗04:01 and DRB4∗01:01 results in greater susceptibility than a single susceptible allele DRB1∗01:01. Download high-res image (93KB) Download full-size image