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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.

Frontiers in immunology

Authors: Antonio José Cabrera-Serrano, María Carretero-Fernández, Begoña Pérez-Rojo, Rob Ter Horst, Marisa Cañadas-Garre, Helena Canhão, Luca Quartuccio, Signe B Sorensen, Bente Glintborg, Ileana Filipescu, Eva Pérez-Pampin, Pablo Conesa-Zamora, Jerzy Swierkot, Alfons A den Broeder, Salvatore de Vita, Eva Rabing Brix Petersen, Yang Li, Marieke J H Coenen, Katarzyna Bogunia-Kubik, Vibeke Andersen, João Eurico Fonseca, Merete Lund Hetland, Miguel Ángel López Nevot, Clementina López-Medina, Fernando Jesús Reyes-Zurita, Mihai G Netea, Alejandro Escudero, Rafael Cáliz, Eduardo Collantes-Estévez, José Manuel Sánchez-Maldonado, Juan Sainz

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 , , , , , , , , and 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 , , , and , while , , , , , and had protective effects. Functional analysis showed that was linked to decreased CCL25 levels (p = 0.00030), and to reduced IL10 production after LPS stimulation (p = 1.3×10). The ZNF322rs6901425G allele was associated with reduced TNFB and increased TGM2 levels (p = 9.60×10 and p = 3.00×), both involved in immune signaling and tissue remodeling. Disease-specific associations were found in , , and . The 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). In contrast, and increased RA risk but were protective in r-axSpA, linked to decreased HO-1 and IL6 (p = 2.43×10, 3.287times;10, 1.18×10). These SNPs also acted as eQTLs for immune-related genes such as , , and .

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.

Copyright © 2026 Cabrera-Serrano, Carretero-Fernández, Pérez-Rojo, ter Horst, Cañadas-Garre, Canhão, Quartuccio, Sorensen, Glintborg, Filipescu, Pérez-Pampin, Conesa-Zamora, Swierkot, den Broeder, de Vita, Brix Petersen, Li, Coenen, Bogunia-Kubik, Andersen, Fonseca, Lund Hetland, López Nevot, López-Medina, Reyes-Zurita, Netea, Escudero, Cáliz, Collantes-Estévez, Sánchez-Maldonado and Sainz.

PMID: 42112340

Participating cluster members