Association Of IL-1α,IL-1β,IL-18 And IL-33 Single Nucleotide Polymorphisms, Serum Level And Systemic Sclerosis

Backgroud Systemic sclerosis(SSc) is a connective tissue disease characterized with fibrosis of skin and/or internal organs. SSc starts as a diffuse vasculopathy, followed by immune activation, low grade inflammation and subsequent tissue fibrosis. The word-wide prevalence of SSc was about 7~489 per million. The specific pathological mechanism of SSc remains incompletely understood, but it was reported that the interaction of gene and environmental factors mainly contributed to the incidence of SSc.The generation of multiple antibodies and abnormal expression of cytokines like IL-1α, IL-1β, IL-4, IL-6, IL-13, IL-17, IL-18 and IL-33 et al. might be involved in the regulation of fibrotic process and damage of the vascular. IL-1α, IL-1β, IL-18, IL-33 are belong to the IL-1 family, and the other members also include IL-1Ra, IL-36α, IL-36β, IL-36γ, IL-36 Ra, IL-37 and IL-38. Our fore study pointed out the potential correlation between IL-1 family and SSc.The serum cytokines expression was regulated by the gene level, and gene single nucleotide polymorphisms of IL-1 family might be related with SSc. As it was reported, gene polymorphisms of IL-1A-889C/T(rs1800587), IL-1B-511C/T(rs16944), IL-18-607C/A(rs1946518) and-137G/C(rs187238), IL-33 rs7044343 were associated with autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, but there is a lack of the association between IL-1A-889C/T(rs1800587), IL-1B-511C/TSSc in Chinese Han population.(rs16944), IL-18-607C/A(rs1946518) and-137G/C(rs187238), IL-33 rs7044343 andThus we performed a case-control study to detect the associations of IL-1α, IL-1β, IL-18 and IL-33 serum level, single nucleotide polymorphisms with systemic sclerosis.PartⅠSerum level of IL-1α, IL-1β, IL-18 and IL-33 in systemic sclerosis patientsAim The purpose of this study is to analyze serum IL-1α, IL-1β, IL-18 and IL-33 expression level in SSc patients, and its relationship with clinical and laboratory data.Methods Totally, 56 patients with SSc(7 male and 49 female) from department of Rheumatology and Immunology of the Affiliated Hospitals to Anhui Medical University were included, and 56 healthy controls(8 male and 48 female). Specific enzyme linked immunosorbent assay(ELISA) kits were used to detect the serum level of IL-1α, IL-1β, IL-18 and IL-33. And all the analysis was completed by SPSS 10.1. The test level α was 0.05.Results(1) No significant difference of IL-1α levels in serum between SSc patients and healthy controls(5.24±0.408 pg/ml versus 4.77±0.332 pg/ml, P=0.211). IL-1β, IL-18 and IL-33 serum levels in SSc patients were higher than healthy controls(IL-1β levels: 47.80±1.799 pg/ml versus 37.98±1.352 pg/ml; IL-18 levels: 158.2±6.687 pg/ml versus 132.4±4.363 pg/ml; IL-33 levels: 43.85±1.250 pg/ml versus 33.11±1.068 pg/ml), and the difference showed a statistical significance(all the P values were less than 0.05).(2) There was no significant associations between the serum level of IL-1α, IL-1β, IL-18 and IL-33 and the clinical and laboratory data(all the P values were greater than 0.05).Conclusion No significant difference of IL-1α levels in serum between SSc patients and healthy controls, while IL-1β, IL-18 and IL-33 serum levels in SSc patients were higher than healthy controls. There was no significant association between the serum level of IL-1α, IL-1β, IL-18 and IL-33 and the clinical and laboratory data.Part Association of ILⅡ-1α, IL-1β, IL-18 and IL-33 single nucleotide polymorphisms and SSc: a case-control study and meta-analysisAim The purpose of this study is to analyze the differences of genotype and allele frequencies of IL-1A-889C/T(rs1800587), IL-1B-511C/T(rs16944), IL-18-607C/A(rs1946518), IL-137G/C(rs187238) and IL-33 rs7044343 between SSc patients and healthy controls. And the association of IL-1A-889C/T(rs1800587), IL-1B-511C/T(rs16944), IL-18-607C/A(rs1946518), IL-18-137G/C(rs187238) and IL-33 rs7044343 gene single nucleotide polymorphisms with clinical features.Methods 58 SSc patients(5 male and 53 female) from department of Rheumatology and Immunology of the Affiliated Hospitals to Anhui Medical University were included. As the control group, 113 healthy volunteers(6 male and 107 female) of Chinese population were recruited. Taq Man allele discrimination assay was performed to detect the genotyping of IL-1A-889C/T(rs1800587), IL-1B-511C/T(rs16944), IL-18-607C/A(rs1946518), IL-18-137G/C(rs187238) and IL-33 rs7044343. And meta-analysis was used to detect the association of the gene polymorphism of IL-1A-889C/T and IL-1B-511C/T and SSc by synthesis analysis. The differences of genotype and allele frequencies between SSc patients and healthy controls were detected by Chi-square or Fisher’s exact test. SPSS 10.01 software was used to perform the statistical analyses. The test level α was 0.05.Results(1) Genotype discrimination results of SSc and healthy controls were both accorded with Hard-Weinberg equilibrium(P>0.05).(2) For gene loci IL-1A-889C/T(rs1800587), genotype frequencies of CC, CT and TT in SSc patients was 19.0%, 60.3% and 20.7%, while 69.0%, 25.7% and 4.4% in healthy controls, and the difference showed statistical significance. The minor allele T of IL-1A-889C/T(rs1800587) in SSc patients showed a higher frequency than controls(OR=2.345, 95%CI: 1.518-3.622, P=0.000); There was a statistical significance in the dominant model(TT+TC versus CC, OR=4.167, 95% CI: 2.016-8.612, P = 0.000). For gene loci IL-18-607C/A(rs1946518), the minor allele C in SSc patients showed a higher frequency than controls(C versus A, OR=1.665, 95%CI: 1.060-2.614, P=0.026), and there was a statistical significance in the dominant model(CC+AC versus AA, OR=2.443, 95%CI: 1.081-5.519, P=0.029).(3) Significant association was found between the distribution of genotype and allele frequencies of IL-1B-511C/T(rs16944), IL-18-137G/C(rs187238), IL-18-607C/A(rs1946518) and IL-33 rs7044343 and clinical and laboratory manifestation, including anti nuclear ribonucleoprotein, erythrocyte sedimentation rate, hematuresis and breath with difficulty.(4) Meta-analysis results showed there was no significant association between IL-1A-889C/T gene polymorphism and SSc. But the comparison of genotype CC versus TT of IL-1B-511C/T showed statistical significance(OR=1.675, 95%CI: 1.029-2.726, P=0.038), as well as allele C versus T(OR=1.354, 95%CI: 1.051-1.745, P=0.019).Conclusion Our study showed IL-1A-889C/T(rs1800587) and IL-18-607C/A(rs1946518) were associated with SSc susceptibility in Chinese Han population, T allele of IL-1A-889C/T(rs1800587) and C allele of IL-18-607C/A(rs1946518) might enhance the risk of the incidence of SSc in Chinese Han population.