Genetics of rheumatoid arthritis: what have we learned?

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5-1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70-74 of the DRβ1 chain are associated with the disease. The HLA molecules carrying these "shared epitope" sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA.

Fig. 1

The HLA-DR4 molecule with the position of the SE sequence. The crystal structure of HLA-DRB1*04:01/DRA1*01:01 complexed with a human collagen II-derived peptide (dark grey circles) shows the peptide-binding groove created by the helical structures of the HLA-DR alpha and beta chain with (indicated in red) the SE at peptide-binding pocket 4 (Polyview-3D)

Fig. 2

Susceptibility genes for RA (Barton et al. ; Begovich et al. ; Chen et al. ; Gregersen et al. , ; Kurreeman et al. ; Plenge et al. , , ; Raychaudhuri et al. , ; Remmers et al. ; Stahl et al. ; Stastny ; Suzuki et al. ; Thomson et al. ; Zhernakova et al. 2011)