Influence of IL10 and TGFB1 Promoter Polymorphisms on Serum Cytokine Levels in Development and Severity of RA

Abstract

In our study, we focused on the role of the immunosuppressive cytokines TGF-β1 and IL-10 in RA and, in particular, the influence of the IL10-1082 A/G (rs1800896) and TGFB1-509C/T (rs1800469) promoter polymorphisms on their levels as a prerequisite for RA and disease activity clinical features. We found significantly higher IL-10 and lower TGF-β1 serum levels in women with RA than in controls. Patients who carried the -1082AA and AG genotypes had significantly higher levels of lnIL-10 compared to GG in contrast to healthy women carrying the same genotypes. The heterozygous -1082AG genotype was less frequent in RA cases (45.4%) than in healthy women (56.1%) and could be a protective factor for RA development (over-dominant model, OR = 0.66 95% CI 0.38–1.57). In addition, RA patients carrying the heterozygous -1082AG genotype were less likely to be anti-CCP positive than those carrying the homozygous AA/GG genotypes (37.1% vs. 62.9%; OR = 0.495. 95% CI 0.238–1.029, p = 0.058). There was no association between TGFB1 -509C/T SNP and susceptibility to RA and no relation between systemic TGF-β1 levels and rs1800469 genotypes. In conclusion, the IL10-1082 genotypes affect the serum levels of IL-10 in women with RA in a different way from that in healthy women and appear to play a role in the genetic predisposition and autoantibody production in the Bulgarian population.

Genetic Variations in IL-1β, TNF-α, and TGF-β Associated with the Severity of Chronic Cervical Spondylitis in Patients

“…However, Min-yu-tu et al showed that the CC-genotype of TGF-β could be protective in the progression of osteoporosis [ 48 ]. Liu C et al showed different findings from ours, where they found TT genotype and T-allele to be significantly associated with the susceptibility to OA, as other studies reported previously [ 30 , 49 , 50 , 51 ], although some studies did not find any association [ 52 ]. The position of TGF-β (-509C/T) is in the negative regulatory region of the TGF-β1 promotor.…”

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A

“…Under the GCAS-approach, we found that the presence of FEIs on study entry ( ) versus their absence ( ) was strongly associated with four CTLA4 -assigned SNPs ( Figure 2 ), with rs231780 yielding the strongest signal ( p =2.3E-5) (Table 2), and suggestively associated with rs7528265, a SNP assigned to the interleukin (IL)-10 gene ( IL10 ) ( p =3.7E-3), which is closely linked to the three other Chr1 genes of the IL10 -superfamily, i.e., IL19 , IL20 , and IL24 encoding IL-19, IL-20, and IL-24 (Table 2). Like NOS2A and B3GNT2 , both CTLA4 and IL10 had previously been implicated in multiple AADs—including, e.g., RA, IDDM, and SLE 58 , 59 , 60 , 61 , 62 , 63 —but both had also been confirmed genetically to play a role in the development of FEIs. 20 , 22 , 23 Located on the long-arm of Chr2, CTLA4 comprises a telomerically-oriented, four-exon-containing transcription unit which spans sense-strand nucleotides 203,867,771–203,873,965 (GRCh38/hg38) ( Figure 3C ) and encodes the T-cell receptor—cytotoxic T-lymphocyte-associated-protein-4 (CTLA4)—that transduces inhibitory signals to down-regulate immune responses.…”

An Elevated IL10 mRNA Combined with Lower TNFA mRNA Level in Active Rheumatoid Arthritis Peripheral Blood

“…Our previous studies demonstrated elevated serum inflammatory cytokines in women with RA with altered cytokine production depending on different treatment regimens [ 13 ]. However, investigation of immunoregulatory IL-10 and TGF-β1 in the same cohort revealed down-regulated systemic TGF-β1 but elevated IL-10 [ 8 ]. Also, we found that some single-nucleotide polymorphisms on promoter regions on IL10 and IL12B genes regulate serum cytokine expression and influence disease occurrence [ 8 , 9 ].…”

“…However, investigation of immunoregulatory IL-10 and TGF-β1 in the same cohort revealed down-regulated systemic TGF-β1 but elevated IL-10 [ 8 ]. Also, we found that some single-nucleotide polymorphisms on promoter regions on IL10 and IL12B genes regulate serum cytokine expression and influence disease occurrence [ 8 , 9 ]. In this regard, the present study exploring the cytokine mRNA expression in the group of RA patients is a continuation of our previous investigations to understand better the involvement of inflammatory and regulatory cytokines in disease development.…”

“…Several genetic, epigenetic, and acquired factors influence a pro-inflammatory context of RA that enables auto-tolerance breaking. Genetic polymorphisms, including single nucleotide polymorphisms (SNPs) in the regulatory part of the cytokine gene, influence cytokine levels [ 8 , 9 , 10 ]. Aberrant epigenetic changes in RA, including deoxyribonucleic acid (DNA) methylation pattern, histone modification, and micro ribonucleic acid (miRNA) expression, have already been identified as factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts but also in the peripheral blood of patients [ 11 ].…”