Abstract
ObjectivesTo find out the genetic association between IL6 and autoimmune arthritis.MethodsWe performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases.ResultsThe MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population.ConclusionOur findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.
Highlights
Interleukin-6 (IL-6), as a proinflammatory cytokine, plays major roles in the inflammation process and the development of the immune system [1, 2]
Potential genetic association between the levels of IL6-signaling, sIL6R, and autoimmune arthritis were detected by using twosample MR analysis (Figure 1)
Casual effects of upregulated IL6-signaling have been found to be positively associated with rheumatoid arthritis (RA) (IVW mode effect=0.325, 95%CI 0.088 to 0.561, p=7.08E-03) and ankylosing spondylitis (AS) (IVW mode effect=1.240, 95%CI 0.495 to 1.980, p=1.1E-03)
Summary
Interleukin-6 (IL-6), as a proinflammatory cytokine, plays major roles in the inflammation process and the development of the immune system [1, 2]. Abnormal immune response could lead to autoimmune arthritis including rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA), which places a great burden on patients by causing joint destruction and even ending up with disability [3, 4]. IL-6 blockade seems to be a therapeutic target for alleviating the process of autoimmune arthritis. Anti-IL-6 signaling drugs such as tocilizumab and siltuximab have been approved for RA and systemic juvenile idiopathic arthritis therapy by the Food and Drug Administration (FDA) [4]. Treating AS or PsA with anti-IL-6 therapy could only relatively alleviate the progression of diseases in some reports [8, 9]
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