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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 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 ten 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 ten SNPs form a common risk haplotype for SLE (p= 1.7 x 10-5; OR= 1.71). 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; OR= 1.59) in cells carrying the risk haplotype for SLE compared to cells with a non-risk haplotype. The risk allele of the SNP rs7582694 in STAT4 correlated to production of antidsDNA antibodies and displayed a multiplicatively increased, 1.82-fold risk of SLE with two independent risk alleles of the IRF5 gene. at Pennsylvania State University on April 27, 2014 http://hmg. oxfordjournals. org/