A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5.
Systemic lupus erythematosus (SLE) is the prototype autoimmune disease where genes regulated by type I interferon (IFN) are over-expressed and contribute to the disease pathogenesis. Because signal transducer and activator of transcription 4 (STAT4) plays a key role in the type I IFN receptor signaling, we performed a candidate gene study of a comprehensive set of single nucleotide polymorphism (SNPs) in STAT4 in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs in STAT4 were associated with SLE, with the strongest signal of association (P = 7.1 x 10(-8)) for two perfectly linked SNPs rs10181656 and rs7582694. The risk alleles of these 10 SNPs form a common risk haplotype for SLE (P = 1.7 x 10(-5)). According to conditional logistic regression analysis the SNP rs10181656 or rs7582694 accounts for all of the observed association signal. By quantitative analysis of the allelic expression of STAT4 we found that the risk allele of STAT4 was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele of STAT4 was over-expressed (P = 8.4 x 10(-5)) in cells carrying the risk haplotype for SLE compared with cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of anti-dsDNA (double-stranded DNA) antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene.
Sigurdsson
Snaevar
S
Molecular Medicine, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
Nordmark
Gunnel
G
Garnier
Sophie
S
Grundberg
Elin
E
Kwan
Tony
T
Nilsson
Olof
O
Eloranta
Maija-Leena
ML
Gunnarsson
Iva
I
Svenungsson
Elisabet
E
Sturfelt
Gunnar
G
Bengtsson
Anders A
AA
Jönsen
Andreas
A
Truedsson
Lennart
L
Rantapää-Dahlqvist
Solbritt
S
Eriksson
Catharina
C
Alm
Gunnar
G
Göring
Harald H H
HH
Pastinen
Tomi
T
Syvänen
Ann-Christine
AC
Rönnblom
Lars
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000974:Antibodies, Antinuclear / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
D000974:Antibodies, Antinuclear; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human