Systematic review and independent validation of genetic factors of radiographic outcome in rheumatoid arthritis identifies a genome-wide association with CARD9.

Objectives: This study aimed to investigate non-HLA genetic mechanisms underlying radiographic severity in rheumatoid arthritis (RA).

Methods: A systematic review of publications reporting non-HLA genetic associations with radiographic severity in RA across ancestries was undertaken. Experimental validation was performed in the Norfolk Arthritis Register, comprising 1407 patients with available genetic and treatment data followed prospectively for up to 10 years, with 2198 longitudinal radiographs. Genome-wide genotyping was performed with Illumina Human Core Exome Array. Radiographic outcomes (presence of erosions; Larsen score) were modelled longitudinally. Fine mapping and functional annotations to refine associations to potential causative loci were undertaken using FUMA, PolyPhen2, and RegulomeDB.

Results: The systematic review identified 102 publications reporting 139 independent associations with radiographic outcome. Association with 15 independent polymorphisms were replicated in the Norfolk Arthritis Register data set, implicating adaptive immune processes (Th1, Th2, and Th17 pathways), cytokine regulation, and osteoclast differentiation. Notably, we refined the association of rs59902911 at the CARD9 locus to an intronic polymorphism within an active enhancer (rs78892335), achieving genome-wide significance and with an effect size exceeding the minimal clinically important difference for each copy of the minor allele (4.78 Larsen units/copy; 95% CI, 3.15-6.41; p = 9.01 × 10^-9). This polymorphism is associated with the expression of CARD9 in immune cells, including B cells.

Conclusions: We provide a comprehensive list of validated genetic associations with RA outcome and demonstrate that non-HLA polymorphisms can associate with radiographic severity independently of disease susceptibility. This highlights the importance of dedicated genetic outcome studies for patient stratification in precision medicine for RA.