TY - JOUR
T1 - Identification of new overlapping and disease-specific genetic risk factors for rheumatoid arthritis and radiographic axial spondyloarthritis
T2 - a meta-analysis of three large European populations and functional characterization
AU - Cabrera-Serrano, Antonio José
AU - Carretero-Fernández, María
AU - Pérez-Rojo, Begoña
AU - Ter Horst, Rob
AU - Cañadas-Garre, Marisa
AU - Canhão, Helena
AU - Quartuccio, Luca
AU - Sorensen, Signe B.
AU - Glintborg, Bente
AU - Filipescu, Ileana
AU - Pérez-Pampin, Eva
AU - Conesa-Zamora, Pablo
AU - Swierkot, Jerzy
AU - den Broeder, Alfons A.
AU - de Vita, Salvatore
AU - Brix Petersen, Eva Rabing
AU - Li, Yang
AU - Coenen, Marieke J.H.
AU - Bogunia-Kubik, Katarzyna
AU - Andersen, Vibeke
AU - Fonseca, João Eurico
AU - Lund Hetland, Merete
AU - López Nevot, Miguel Ángel
AU - López-Medina, Clementina
AU - Reyes-Zurita, Fernando Jesús
AU - Netea, Mihai G.
AU - Escudero, Alejandro
AU - Cáliz, Rafael
AU - Collantes-Estévez, Eduardo
AU - Sánchez-Maldonado, José Manuel
AU - Sainz, Juan
N1 - Publisher Copyright:
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.
PY - 2026
Y1 - 2026
N2 - 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.
AB - 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.
KW - ankylosing spondylitis
KW - functional characterization
KW - genetic variants
KW - overlapping and disease-specific genetic markers
KW - rheumatoid arthritis
UR - https://www.scopus.com/pages/publications/105038483389
U2 - 10.3389/fimmu.2026.1637735
DO - 10.3389/fimmu.2026.1637735
M3 - Journal article
C2 - 42112340
AN - SCOPUS:105038483389
SN - 1664-3224
VL - 17
SP - 1637735
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1637735
ER -