Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.
Among eight SSc-associated susceptibility polymorphisms which were applied for meta-analysis, IRF5rs2004640 polymorphism (OR 1.12; 95% CI 1.02-1.22, P = 1.39 × 10<sup>-2</sup>), STAT4 rs7574865 polymorphism (OR 1.25; 95% CI 1.07-1.47, P = 5.3 × 10<sup>-3</sup>), IRAK1 rs1059702 polymorphism (OR 1.20; 95% CI 1.05-1.37, P = 0.007), and CTGF G-945C polymorphism (OR 1.42; 95% CI 1.18-1.71, P = 0.002) are associated with PF status in SSc, while TNFAIP3 rs5029939, CD226 rs763361, CD247 rs2056626, and IRF5rs10488631 polymorphisms are not.
An additive effect of the STAT4 rs7574865 T allele and the IRF5rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc.
An additive effect of the STAT4rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc.
We examined the relationship between five gene polymorphisms [cytotoxic T lymphocyte associated antigen 4 (CTLA-4) -1722T/C, CTLA-4 -318C/T, CTLA-4 +49A/G, angiotensin-converting enzyme I/D, STAT-4rs7574865] and susceptibility to SSc.
An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.
We identified an IRF5 risk haplotype "R" (p(adj) = 0.024, OR 1.23, 95% CI 1.07-1.40) and a mirrored protective haplotype "P" (p(adj) = 8.8 x 10(-3), OR 0.78, 95% CI 0.68-0.90) for SSc susceptibility.
The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc.
Since IRF5, STAT4, and IRAK1 are important regulatory factors in the control of innate immune responses and CTGF is involved in the synthesis of extracellular matrix, these results suggest a role of the innate immunity and matrix compounds in the pathogenesis of PF in SSc.
Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis).
We demonstrated that protein expression of the TCR zeta chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc).
Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc.