Exploring the causal relationship between inflammatory cytokines and C-reactive protein levels and atopic dermatitis: a two-way two-sample Mendelian randomization study
Authors: Lin Li , Ma Yizhao , Niu Zuohu , Zhang Bo , Yu Fangning , Xu Xuying 
Published: September 2024

Objective: Atopic dermatitis (AD) is an allergic inflammatory skin disease. Changes in circulating inflammatory proteins are reflected in the entire process of AD progression, and its pathophysiology is still unclear. This Mendelian randomization study was conducted to further evaluate the role of circulating inflammatory proteins in AD.
Methods: This study investigated the potential causal relationship between circulating inflammatory proteins and AD. We used a two-sample Mendelian randomization (MR) method to analyze data from a large-scale genome-wide association study to explore the relationship between 91 circulating inflammatory proteins, 41 inflammatory factors, and CRP and AD. The inverse variance weighted method was mainly used to evaluate the causal relationship between exposure and outcome based on the effect indicator odds ratio (OR) and 95% confidence interval (CI). In addition, MR-Egger, weighted median, simple model, weighted model and MR-PRESSO multiple sensitivity analyses were applied to strengthen the final results. The leave-one-out method, heterogeneity test, and horizontal gene pleiotropy test were used to verify the stability and reliability of the results.
Results: Forward MR analysis showed that there was a significant correlation between AD risk and changes in the levels of multiple inflammatory proteins at different p-value thresholds, among which increased levels of interleukin-18 receptor 1 were found to increase the risk of AD, which was significant in all three groups of analysis (P IVW<0.05); increased levels of C-X-C motif chemokine 9 and Fms-related tyrosine kinase 3 ligand were found to reduce AD risk at P<5×10-8 and p<5×10-7 thresholds; increased levels of C-X-C motif chemokine 11 were found to be associated with a reduced risk of AD at P<5×10-8 and P<5×10-6 thresholds (P IVW<0.05). Reverse MR analysis showed that increased AD risk was associated with decreased levels of AXIN-1, natural killer cell receptor 2B4, interleukin-1 receptor subunit α, and interleukin-33 (P IVW<0.05). In addition, increased AD risk was associated with increased Cystatin D levels (P IVW<0.05). In the 41 inflammatory factor data sets, increased AD risk may be associated with increased IL18 levels (P IVW=0.036) and MIG levels (P IVW=0.046). No significant heterogeneity and horizontal pleiotropy were observed in the analysis. After verification MR analysis, it was found that there was a significant association between the levels of inflammatory proteins such as Fms-related tyrosine kinase 3 ligand, interleukin 18 receptor 1, C-X-C motif chemokine 9, and tumor necrosis factor ligand superfamily member 14 and AD risk, and there was consistency between different P value thresholds. Bidirectional MR showed that there was a complex bidirectional causal relationship between interleukin 18 receptor 1 levels and AD. The leave-one-out analysis showed that the results were stable, there were no instrumental variables that had a strong impact on the results, and the leave-one-out method verified the robustness of the results. There was heterogeneity test and horizontal pleiotropy in the reverse causal relationship between the level of tumor necrosis factor ligand superfamily member 14 and the AD validation set.
Conclusion: The results of MR analysis indicate a potential causal relationship between circulating inflammatory proteins and AD. This study provides a new approach for exploring the biological mechanisms of AD in the future and proposes possible therapeutic targets. Further research is needed to confirm these results and understand the specific role of these proteins in AD, and to provide reference value for future studies on the relationship between circulating inflammatory proteins and AD.