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. 2021 Sep 3:12:707617.
doi: 10.3389/fimmu.2021.707617. eCollection 2021.

Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific

Jianqiao Hong  1   2   3 , Zihao Qu  1   2   3 , Xiaoxiao Ji  1   2   3 , Congsun Li  1   2   3 , Geng Zhang  1   2   3 , Ciliang Jin  4 , Jie Wang  1   2   3 , Yongxing Zhang  1   2   3 , Yue Shen  1   2   3 , Jiahong Meng  1   2   3 , Chenhe Zhou  1   2   3 , Chaohua Fang  5 , Wei Wang  1   2   3 , Shigui Yan  1   2   3
Affiliations

Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific

Jianqiao Hong et al. Front Immunol. .

Abstract

Objectives: To find out the genetic association between IL6 and autoimmune arthritis.

Methods: We 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.

Results: The 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.

Conclusion: Our 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.

Keywords: ADAR; IL6; Mendelian randomization; autoimmune arthritis; sIL6R.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Graphical diagram of the Mendelian randomization analysis between IL6 and risk of autoimmune arthritis. RA, rheumatoid arthritis; AS, ankylosing spondylitis; PsA, psoriatic arthritis.
Figure 2
Figure 2
Forest plot of the causal effects of IL6-signaling and sIL6R on autoimmune arthritis.
Figure 3
Figure 3
Forest plot of the causal association between IL6-signaling/sIL6R and autoimmune arthritis by sex.
Figure 4
Figure 4
Expression of ADAR in RA or PsA from GEO datasets GSE61281 (A) and GSE74143 (B). con, control; psa, psoriatic arthritis; ps, psoriasis; RA, rheumatoid arthritis; F, female; M, male. Data from all bar graphs are presented as mean ± SEM. (*P < 0.05, ****P < 0.0001, n.s, not significant).
Figure 5
Figure 5
Regional plot of the genetic variants at 1q21.3 and their association with autoimmune arthritis.
See this image and copyright information in PMC

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