The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype.
BACKGROUND
Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors.


OBJECTIVE
As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis.


METHODS
1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP).


RESULTS
Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1×10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10(-5) and T=19.6%, p=3.66×10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively.


CONCLUSIONS
This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.
Dawidowicz
Karen
K
GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of the AutoCure European Consortium, Evry-Genopole cedex, France.
Allanore
Yannick
Y
Guedj
Mickaël
M
Pierlot
Céline
C
Bombardieri
Stefano
S
Balsa
Alejandro
A
Westhovens
René
R
Barrera
Pilar
P
Alves
Helena
H
Teixeira
Vitor Hugo
VH
Petit-Teixeira
Elisabeth
E
van de Putte
Leo
L
van Riel
Piet
P
Prum
Bernard
B
Bardin
Thomas
T
Meyer
Olivier
O
Cornélis
François
F
Dieudé
Philippe
P
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012217:Rheumatoid Factor / Q000097:blood; D055815:Young Adult
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D012217:Rheumatoid Factor