Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis

Abstract

Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα concentrations in patients with SLE (n=117) or RA (n=164) and in inflammatory disease-free control subjects (n=172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2 and CD40L in SLE and DRB1, NOD2 and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1 and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.

The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort

“…In reverse, PTPN2 is an important inhibitor of the secretion of proinflammatory cytokines like TNF. This has been confirmed by detecting significantly higher TNF levels in PTPN2-deficient mice [30,31] . We have previously shown that the presence of the PTPN2 SNP rs1893217 causes a diminished function of PTPN2 protein [4] .…”

“…In that way, the inhibitory signals for TNF in the negative feedback loop are weakened and consequently more TNF is released. TNF reaches higher serum levels in patients with autoimmune diseases and is an essential pro-inflammatory cytokine that maintains chronic inflammation [31][32][33] . By blocking the excessive TNF production with anti-TNF agents, this viscous inflammation-maintaining cycle can be interrupted.…”

Long noncoding RNAs in autoimmune diseases

“…If left untreated, the disease manifests as sustained synovitis and erosion of articular cartilage and surrounding bone. Some proinflammatory cytokines, such as TNFα, interleukin 1B (IL‐1b), and IL‐6, are closely related to the incidence of RA …”

“…Some proinflammatory cytokines, such as TNFα, interleukin 1B (IL-1b), and IL-6, are closely related to the incidence of RA. [74][75][76] Müller et al analyzed lncRNA transcription in a microarray-based experiment of CD14(+) monocytes isolated from peripheral blood cells of RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy. These researchers found that the expression of 7419 lncRNAs was changed by either IL-6 or TNF-α, and 85 of these lncRNAs exhibited significantly altered expression.…”

Role of Stem Cell–Like Memory T Cells in Systemic Lupus Erythematosus

“…Serum levels of IL‐6 are significantly higher in SLE patients than in HCs . IL‐6 favors development of Tfh cells.…”