Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset.
BACKGROUND
Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort.


RESULTS
Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74-0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63-12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74-1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75-1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction.


CONCLUSIONS
Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.
Glas
Jürgen
J
Department of Medicine II-Grosshadern, University of Munich, Munich, Germany.
Seiderer
Julia
J
Nagy
Melinda
M
Fries
Christoph
C
Beigel
Florian
F
Weidinger
Maria
M
Pfennig
Simone
S
Klein
Wolfram
W
Epplen
Jörg T
JT
Lohse
Peter
P
Folwaczny
Matthias
M
Göke
Burkhard
B
Ochsenkühn
Thomas
T
Diegelmann
Julia
J
Müller-Myhsok
Bertram
B
Roeske
Darina
D
Brand
Stephan
S
D017668:Age of Onset; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D003424:Crohn Disease / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics*
C515500:IL23R protein, human; D018123:Receptors, Interleukin; D050797:STAT4 Transcription Factor
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