Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis.
OBJECTIVE
Previous studies have shown either a lack of effect of IRF5 polymorphisms or an association of the IRF5 gene in only a minor subset of rheumatoid arthritis (RA) patients in whom anti-citrullinated protein antibodies (ACPAs) are absent. The present study was undertaken to investigate the role of genetic variation in IRF5 in susceptibility to RA.


METHODS
Nine IRF5 single-nucleotide polymorphisms (SNPs) were studied in 1,338 patients with RA and 1,342 control subjects in analyses of exploratory and replication sample collections, with stratification according to sex and by the presence or absence of ACPAs, rheumatoid factor, the shared epitope, the 620W PTPN22 allele, and erosions. A meta-analysis that included results from previous studies was also carried out.


RESULTS
Our findings together with those from previous studies, in a total of 4,620 RA patients and 3,741 controls, showed a significant association of the rs2004640 IRF5 SNP in RA patients as a whole (odds ratio [OR] 0.88, 95% confidence interval [95% CI] 0.83-0.94; P = 6.5 x 10(-5) versus controls). This association was stronger in ACPA- patients, but was also present in ACPA+ patients (from 3 sample collections). Further analysis of our exploratory sample collection showed that only patients in the ACPA+ and SE- group lacked an association with IRF5 SNPs. All of the remaining RA patients (ACPA- or SE+) showed a strong association with IRF5 SNPs, which followed a complex pattern of opposing effects mediated by independent haplotypes. The susceptibility haplotype showed an OR of 1.8 (95% CI 1.4-2.3; P = 1.2 x 10(-6) versus controls), whereas the protective haplotype showed an OR of 0.76 (95% CI 0.6-0.98; P = 0.046 versus controls).


CONCLUSIONS
IRF5 polymorphisms seem to influence RA susceptibility in a large subgroup of patients, following a pattern of association very similar to that described in patients with systemic lupus erythematosus.
Dieguez-Gonzalez
Rebeca
R
Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Calaza
Manuel
M
Perez-Pampin
Eva
E
de la Serna
Arturo Rodriguez
AR
Fernandez-Gutierrez
Benjamin
B
Castañeda
Santos
S
Largo
Raquel
R
Joven
Beatriz
B
Narvaez
Javier
J
Navarro
Federico
F
Marenco
Jose Luis
JL
Vicario
Jose Luis
JL
Blanco
Francisco J
FJ
Fernandez-Lopez
Jesus Carlos
JC
Caliz
Rafael
R
Collado-Escobar
María Dolores
MD
Carreño
Luis
L
Lopez-Longo
Javier
J
Cañete
Juan D
JD
Gomez-Reino
Juan J
JJ
Gonzalez
Antonio
A
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors