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

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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.

Details

Authors
  • Snaevar Sigurdsson
  • Gunnel Nordmark
  • Sophie Garnier
  • Elin Grundberg
  • Tony Kwan
  • Olof Nilsson
  • Maija-Leena Eloranta
  • Iva Gunnarsson
  • Elisabet Svenungsson
  • Gunnar Sturfelt
  • Anders A. Bengtsson
  • Andreas Jonsen
  • Lennart Truedsson
  • Solbritt Rantapaa-Dahlqvist
  • Catharina Eriksson
  • Gunnar Alm
  • Harald H. H. Goring
  • Tomi Pastinen
  • Ann-Christine Syvanen
  • Lars Ronnblom
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)2868-2876
JournalHuman Molecular Genetics
Volume17
Issue number18
Publication statusPublished - 2008
Publication categoryResearch
Peer-reviewedYes