Genetics of rheumatoid arthritis susceptibility, severity, and treatment response

Abstract

A decade after the first genome-wide association study in rheumatoid arthritis (RA), a plethora of genetic association studies have been published on RA and its clinical or serological subtypes. We review the major milestones in the study of the genetic architecture of RA susceptibility, severity, and response to treatment. We set the scientific context necessary for non-geneticists to understand the potential clinical applications of human genetics and its significance for a stratified approach to the management of RA in the future.

Fig. 1

Cumulative proportion of the observed variance in rheumatoid arthritis susceptibility explained thus far by genetic susceptibility loci identified to date across Asian and Caucasian cohorts. Odds ratios (left axis) for RA genetic susceptibility loci are presented in the approximate chronological order of discovery (new associations from the study by Okada [41] are shown in 2013). The proportion of the variance explained (right axis) is indicated by the black line. A 0.5% disease prevalence was assumed for calculation. In the beginning of 2017, approximately 19.5% of phenotypic variance had been accounted for genetically. On average, every SNP outside the HLA explains 0.08% of the total phenotypic variance. For simplification, every locus is represented once, even if multiple independent effects were identified (except for TNFAIP3 and TRAF1/CDK5RAP2, where two independent effects are reported). The OR for the MHC represents the largest OR for a SNP across the MHC, but the % explained variance has been calculated for multiple independent effects across the MHC. Abbreviation: RA rheumatoid arthritis, OR odds ratio

Fig. 2

Major (red) and minor (green) pathways explaining the statistical association between genetic markers of clinical outcome variables in RA (acyclic graphs from mediation analysis [81]) (Color figure online)