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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) inSTAT4in Swedish patients with SLE. We found that 10 out of 53 analyzed SNPs inSTAT4were 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 ofSTAT4we found that the risk allele ofSTAT4was over-expressed in primary human cells of mesenchymal origin, but not in B-cells, and that the risk allele ofSTAT4was 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 inSTAT4correlated 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 theIRF5(interferon regulatory factor 5) gene.

human molecular genetics

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