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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

Sigurdsson, Snaevar; Nordmark, Gunnel; Garnier, Sophie; Grundberg, Elin; Kwan, Tony; Nilsson, Olof; Eloranta, Maija-Leena; Gunnarsson, Iva; Svenungsson, Elisabet and Sturfelt, Gunnar, et al. (2008) In Human Molecular Genetics 17(18). p.2868-2876
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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
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Human Molecular Genetics
volume
17
issue
18
pages
2868 - 2876
publisher
Oxford University Press
external identifiers
  • wos:000258863200010
  • scopus:50849101942
ISSN
0964-6906
DOI
10.1093/hmg/ddn184
language
English
LU publication?
yes
id
fa79b2cd-fdbf-4f0e-8a59-0b3510c10f8a (old id 1247802)
date added to LUP
2008-11-10 11:20:26
date last changed
2017-09-03 03:56:34
@article{fa79b2cd-fdbf-4f0e-8a59-0b3510c10f8a,
  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.},
  author       = {Sigurdsson, Snaevar and Nordmark, Gunnel and Garnier, Sophie and Grundberg, Elin and Kwan, Tony and Nilsson, Olof and Eloranta, Maija-Leena and Gunnarsson, Iva and Svenungsson, Elisabet and Sturfelt, Gunnar and Bengtsson, Anders A. and Jonsen, Andreas and Truedsson, Lennart and Rantapaa-Dahlqvist, Solbritt and Eriksson, Catharina and Alm, Gunnar and Goring, Harald H. H. and Pastinen, Tomi and Syvanen, Ann-Christine and Ronnblom, Lars},
  issn         = {0964-6906},
  language     = {eng},
  number       = {18},
  pages        = {2868--2876},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  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},
  url          = {http://dx.doi.org/10.1093/hmg/ddn184},
  volume       = {17},
  year         = {2008},
}