Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis.
OBJECTIVE
To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA).


METHODS
Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP).


RESULTS
Four of the 5 SNPs located in the 5' region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of approximately 0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort.


CONCLUSIONS
Given the fact that anti-CCP-negative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.
Sigurdsson
Snaevar
S
Uppsala University, Uppsala, Sweden.
Padyukov
Leonid
L
Kurreeman
Fina A S
FA
Liljedahl
Ulrika
U
Wiman
Ann-Christin
AC
Alfredsson
Lars
L
Toes
René
R
Rönnelid
Johan
J
Klareskog
Lars
L
Huizinga
Tom W J
TW
Alm
Gunnar
G
Syvänen
Ann-Christine
AC
Rönnblom
Lars
L
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012016:Reference Values; D013548:Sweden; D053634:TYK2 Kinase / Q000235:genetics
D001323:Autoantibodies; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D010456:Peptides, Cyclic; D053634:TYK2 Kinase; C070139:TYK2 protein, human