Human Molecular Genetics Advance Access originally published online on June 25, 2008
Human Molecular Genetics 2008 17(18):2868-2876; doi:10.1093/hmg/ddn184
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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
1 Molecular Medicine, Department of Medical Sciences 2 Section of Rheumatology, Department of Medical Sciences 3 Department of Surgical Sciences, Uppsala University, SE-75185 Uppsala, Sweden 4 McGill University and Genome Quebec Innovation Centre 5 Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1A4, Canada 6 Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, SE-77176 Stockholm, Sweden 7 Department of Rheumatology 8 Institute of Laboratory Medicine Section of MIG, Lund University, SE-22100 Lund, Sweden 9 Department of Rheumatology 10 Department of Clinical Immunology, University Hospital, SE-90185 Umeå, Sweden 11 Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden 12 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
* To whom correspondence should be addressed at: Molecular Medicine, Department of Medical Sciences, Uppsala University, Entrance 70, Research Department 2, 3rd Floor, Uppsala University Hospital, 75185 Uppsala, Sweden. Tel: +46 186112959; Fax: +46 18553601; Email: ann-christine.syvanen{at}medsci.uu.se
Received March 16, 2008; Revised June 14, 2008; Accepted June 23, 2008
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.
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