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. 2024 May 27:15:1404260.
doi: 10.3389/fimmu.2024.1404260. eCollection 2024.

Genetically predicted associations between circulating cytokines and autoimmune diseases: a bidirectional two-sample Mendelian randomization

Jie Jie  1 , Yonglu Gong  1 , Songquan Luo  1 , Xing Yang  1 , Kaiyun Guo  1
Affiliations

Genetically predicted associations between circulating cytokines and autoimmune diseases: a bidirectional two-sample Mendelian randomization

Jie Jie et al. Front Immunol. .

Abstract

Objectives: Previous studies have indicated a correlation between cytokines and autoimmune diseases. yet the causality remains uncertain. Through Mendelian Randomization (MR) analysis, we aimed to investigate the causal relationships between genetically predicted levels of 91 cytokines and three autoimmune diseases: Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), and Hashimoto's Thyroiditis (HT).

Methods: A bidirectional two-sample MR approach was utilized to assess the causal relationships between cytokines and MS, SLE, and HT. The datasets included 47,429 MS cases and 68,374 controls, 5,201 SLE cases and 9,066 controls, and 16,191 HT cases with 210,612 controls. Data on 91 cytokines comprised 14,824 participants. Causal analyses primarily employed inverse variance weighted, weighted median, and MR-Egger methods, with sensitivity analyses including heterogeneity and pleiotropy assessment.

Results: Genetically predicted levels of IL-18 (OR = 0.706; 95% C.I. 0.538-0.925), ADA (OR = 0.808; 95% C.I. 0.673-0.970), and SCF (OR = 0.898; 95% C.I. 0.816-0.987) were associated with a decreased risk of MS. IL-4 (OR = 1.384; 95% C.I. 1.081-1.771), IL-7 (OR = 1.401; 95% C.I. 1.010-1.943), IL-10RA (OR = 1.266; 95% C.I. 1.004-1.596), CXCL5 (OR = 1.170; 95% C.I. 1.021-1.341), NTN (OR = 1.225; 95% C.I. 1.004-1.496), FGF23 (OR = 0.644; 95% C.I. 0.460-0.902), and MCP4 (OR = 0.665; 95% C.I. 0.476-0.929) were associated with SLE risk. CDCP1 (OR = 1.127; 95% C.I. 1.008-1.261), IL-33 (OR = 0.852; 95% C.I. 0.727-0.999), and TRAIL (OR = 0.884; 95% C.I. 0.799-0.979) were associated with HT risk. Bidirectional MR results suggest the involvement of CCL19, IL-13, SLAM, ARTN, Eotaxin, IL-22RA1, ADA, and MMP10 in the downstream development of these diseases.

Conclusions: Our findings support causal relationships between certain cytokines and the risks of MS, SLE, and HT, identifying potential biomarkers for diagnosis and prevention. Additionally, several cytokines previously unexplored in these autoimmune disease contexts were discovered, laying new groundwork for the study of disease mechanisms and therapeutic potentials.

Keywords: cytokine; hashimoto’s thyroiditis; mendelian randomization; multiple sclerosis; systemic lupus erythematosus.

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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
Overview and research content of MR. (A) Principle and process of TwoSample MR. (B) Specific steps ofTwoSample MR.
Figure 2
Figure 2
Heatmaps of the different MR analysis methods for the association between cytokines and the risk of three autoimmune diseases.
Figure 3
Figure 3
Forest plots of cytokines and the risk of three autoimmune diseases.
Figure 4
Figure 4
Forest plots showing the effects of three autoimmune diseases on cytokines.
See this image and copyright information in PMC

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