STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk

Abstract

Objectives To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5’-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

“…We found no significant association of any genotype with mRNA levels of STAT4a and STA4b among 30 pSS patients. A lack of power does not likely explain the discrepancies between our results and those from Abelson et al 8 because no trend effect was observed. We wondered whether the functional consequences of STAT4 risk allele might be explained by an environmental upregulation of STAT4 among pSS patients.…”

“…Moreover, the significant association of both STAT4 and IRF5 polymorphisms has been also reported for other autoimmune diseases or inflammatory conditions, such as systemic sclerosis, 14 rheumatoid arthritis, 15 lupus. 8,11,[15][16][17][18] Interestingly, all these autoimmune diseases could be, to some extent type 1 IFN driven. This study provides additional data suggesting that STAT4 and IRF5 function independently on pSS genetic susceptibility, with an additive effect but with no epistatic interaction between both genes, which confirms the findings from Nordmark et al 6 in patients of North European ancestry.…”

“…Few functional studies of STAT4 rs7582694 polymorphism have been performed. Abelson et al 8 reported a modest but significant correlation between STAT4 rs7574865 polymorphism (in complete LD with STAT4 rs7582694) and STAT4a mRNA level in PBMCs from 73 healthy volunteers. Sigurdsson et al 17 reported an increased expression of the risk allele of STAT4b in primary cells of mesenchymal origin (osteoblasts).…”

“…STAT4b mRNA level was about 10-fold lower than that of STAT4a, as was previously reported. 8 STATa and STAT4b mRNA levels in PBMCs were not associated with rs7582694 genotype (P ¼ 0.99 and P ¼ 0.17, respectively) (Figures 2a and b). Analysis of STAT1 mRNA expression level by STAT4 rs7582694 genotype We hypothesized that STAT4 rs7582694 polymorphism could be in high LD with a functional polymorphism located in the nearby STAT1 locus.…”

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].…”