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

• Published in: Human molecular genetics 2008-09, Vol.17 (18), p.2868-2876
• Main Authors: Sigurdsson, Snaevar, Nordmark, Gunnel, Garnier, Sophie, Grundberg, Elin, Kwan, Tony, Nilsson, Olof, Eloranta, Maija-Leena, Gunnarsson, Iva, Svenungsson, Elisabet, Sturfelt, Gunnar, Bengtsson, Anders A., Jönsen, Andreas, Truedsson, Lennart, Rantapää-Dahlqvist, Solbritt, Eriksson, Catharina, Alm, Gunnar, Göring, Harald H.H., Pastinen, Tomi, Syvänen, Ann-Christine, Rönnblom, Lars
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antibodies, Antinuclear - blood; Basic Medicine; Biological and medical sciences; Case-Control Studies; Child; European Continental Ancestry Group - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Humans; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Life Sciences; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Male; Medical and Health Sciences; Medical Genetics; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Molecular and cellular biology; Polymorphism, Single Nucleotide; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; STAT4 Transcription Factor - genetics; STAT4 Transcription Factor - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddn184

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 × 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 × 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 × 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.