title: 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.
abstract: 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.
authors.affiliation: Molecular Medicine, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Olof
authors.initials: O
authors.lastname: Nilsson
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Catharina
authors.initials: C
authors.lastname: Eriksson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Alm
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
mesh_terms: 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
chemical_list: D000974:Antibodies, Antinuclear; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human