Identification of new overlapping and disease-specific genetic risk factors for rheumatoid arthritis and radiographic axial spondyloarthritis: a meta-analysis of three large European populations and functional characterization

Introduction: This study conducted a meta-analysis across three large European cohorts (UKBB, FinnGen, and REPAIR), including 12,660 rheumatoid arthritis (RA) cases, 2,446 radiographic axial spondyloarthritis (r-axSpA) cases, and over 530,000 shared controls. Methods: Ten independent SNPs in CARMIL1, GRM4, ITPR3, PRSS16, ZNF322, HTT, IKZF1, MANEA, and MGAM2 were analyzed, and functional characterization was performed through cytokine and protein assessments as well as eQTL analyses. Results: Ten independent SNPs were significantly associated with both RA and r-axSpA. Risk alleles included HTTrs363075A, IKZF1rs12718261A, MANEArs72920280T, and MGAM2rs73158426G, while CARMIL1rs72831267C, GRM4rs2495964G, ITPR3rs77601296A, ITPR3rs9469540T, PRSS16rs72843633T, and ZNF322rs6901425G had protective effects. Functional analysis showed that GRM4rs2495964G was linked to decreased CCL25 levels (p = 0.00030), and ITPR3rs9469540T to reduced IL10 production after LPS stimulation (p = 1.3×10-4). The ZNF322rs6901425G allele was associated with reduced TNFB and increased TGM2 levels (p = 9.60×10-4 and p = 3.00×10-4), both involved in immune signaling and tissue remodeling. Disease-specific associations were found in BTN2A1, BTN3A2, and H2BC11. The BTN2A1rs1977199A allele was protective in RA (OR = 0.93) but increased r-axSpA risk (OR = 1.23), and was associated with reduced IL22 (p = 0.00016) and elevated HO-1 in obese individuals (p = 6.73×10-6). In contrast, BTN3A2rs9393716G and H2BC11rs66462181C increased RA risk but were protective in r-axSpA, linked to decreased HO-1 and IL6 (p = 2.43×10-5, 3.287times;10-4, 1.18×10-4). These SNPs also acted as eQTLs for immune-related genes such as BTN3A2, HMGN4, and TRIM38. Discussion: Our findings highlight novel shared and disease-specific variants and key immunoregulatory mediators-IL10, IL22, IL6, CCL25, and HO-1-offering insights for disease stratification and therapeutic targeting.