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 HTT rs363075A , IKZF1 rs12718261A , MANEA rs72920280T , and MGAM2 rs73158426G , while CARMIL1 rs72831267C , GRM4 rs2495964G , ITPR3 rs77601296A , ITPR3 rs9469540T , PRSS16 rs72843633T , and ZNF322 rs6901425G had protective effects. Functional analysis showed that GRM4 rs2495964G was linked to decreased CCL25 levels (p = 0.00030), and ITPR3 rs9469540T 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 BTN2A1 rs1977199A 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, BTN3A2 rs9393716G and H2BC11 rs66462181C 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.