The Genetic Architecture of Rheumatoid Arthritis: From Susceptibility to Clinical Subphenotype Associations

Antonio      Julia; Sara      Marsal

Abstract

Rheumatoid Arthritis (RA) is the most common chronic inflammatory disease of the joints and is characterized by a complex genetic architecture. In recent years, a substantial advance has been performed in the identification of the genes that increase the risk to develop RA. Genome-Wide Association Studies (GWAS) have allowed the characterization of more than 40 new susceptibility genes and the confirmation of a marked differential genetic background between patients expressing anti-cyclic citrullinated peptide antibodies (ACPA, approximately 80% of all RA patients) and ACPA negative RA patients. GWAS have also confirmed the existence of a common genetic basis between RA and other autoimmune diseases and the overrepresentation of specific biological pathways like antigen presentation and TNF signaling. Dense genotyping analysis has also allowed the detailed characterization of the different association signals within the HLA region, the strongest risk locus for RA. In the present manuscript, we also review the most recent advances in the genetics of clinically relevant subphenotypes in RA which are the response to treatment and the severity of the disease. In the next years the increasing ability to characterize the DNA variation and the availability of well characterized patient cohorts will be critical to translate genetic information into the much awaited personalized medicine in RA.

Keywords: ACPA, Disease severity, Genetics, Risk, GWAS, HLA, Pharmacogenetics, Rheumatoid Arthritis.