Role of Circulating Inflammatory Proteins in Chronic Hepatitis B: A Two-Sample Mendelian Randomization Study.

Background : Alterations in circulating inflammatory proteins are strongly associated with the progression of chronic hepatitis B (Chon B); however, the nature of this causal relationship remains unclear. Therefore, we conducted two-sample Mendelian randomization (MR) to explore the association between circulating inflammatory proteins and CHB. Methods : Data for 91 circulating inflammatory proteins, including interleukin (IL)-10, tumor necrosis factor-alpha, and two CHB databases were sourced from the genome-wide association studies (GWAS) catalog and International Epidemiology Unit (IEU) Open GWAS project, respectively. MR analysis was performed using inverse variance weighting and several robustness, heterogeneity, and directionality checks, including MR-Egger, Cochran’s Q, MR-PRESSO, leave-one-out, and Steiger analyses. The variability of MR estimates for overlapping circulating inflammatory proteins across CHB datasets were evaluated using single nucleotide polymorphism (SNP) annotations of genes potentially linked to CHB infection. Results : We identified 4,044 SNPs associated with CHB and circulating inflammatory proteins; nine proteins correlated with CHB in the ebi-a-GCST90018804 dataset, whereas seven associated with CHB in the bbj-a-99 dataset. Heterogeneity assessment in both datasets excluded proteins with significant heterogeneity and confirmed the hypothesized direction of causality using Steiger’s test. Meta-analysis revealed that IL-13 was associated with an increased CHB risk, whereas monocyte chemoattractant protein-3 (MCP-3) was associated with a decreased risk; these effects were consistent across the two datasets. An additional 32 genes associated with CHB infection were identified. Conclusion : IL-13 and MCP-3 demonstrate a causal relationship with CHB; they hold promise as inflammatory markers of CHB risk and potential targets for future therapeutic strategies against this disease.