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

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 × 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.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

“…Interestingly, higher ORs were reported in samples of European origin from patients with severe disease manifestations for this gene. 11,12 The higher OR found in our Asian populations compared to those in Caucasians on rs7574865 may be a reflection of the disease severity in Asians. Our data on the subphenotype stratification are largely consistent with the findings by Taylor et al, 11 which we believe, with increased sample size, may provide further evidence on the stronger association of rs7574865 with severe phenotypes of the disease, such as hematologic disorder, nephritis and ds-DNA antibody production.…”

“…[8][9][10] SNP rs7574865 was found to be associated with lupus nephritis, ds-DNA antibody production and age of onset. 11,12 In the GWA study by Hom et al, 7 rs7574865 in STAT4 showed highly significant association with SLE risk, with a P-value only second to variants in the human leukocyte antigen locus. In addition to rs7574865, both Harley et al 8 and Hom et al 7 showed that rs7601754 was also significantly associated with SLE.…”

Antimalarial drugs inhibit IFNα-enhanced TNFα and STAT4 expression in monocytes: Implication for systemic lupus erythematosus

“…Moreover, gene polymorphisms at the interferon regulatory factor 5 (IRF5), a major mediator of TLR-triggered expression of type I IFN [53] and other proinflammatory cytokines, including TNFa [54], act additively with STAT4 genotype to increase the risk for SLE [13,55]. This fact could be explained by the functional link between both molecules, since the risk allele of STAT4 determines a higher frequency of anti-dsDNA antibodies in SLE patients, allowing a continued type I IFN stimulation of the STAT4-dependent autoimmune response [13,53].…”

“…This fact could be explained by the functional link between both molecules, since the risk allele of STAT4 determines a higher frequency of anti-dsDNA antibodies in SLE patients, allowing a continued type I IFN stimulation of the STAT4-dependent autoimmune response [13,53].…”

“…Following activation, human STAT4 binds to regulatory regions of several genes to induce proinflammatory cell-mediated immunity [11]. Interestingly, STAT4 variants are associated with susceptibility to SLE [12,13] and the STAT4 risk allele is associated with nephritis and antibodies to double-stranded DNA, two clinical features linked to the severity and activity of the disease [14].…”