A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B

Abstract

ABSTRACT Objectives: Pegylated interferon alfa (PegIFNα) has limited efficacy in patients with chronic hepatitis B (CHB). Because single-nucleotide polymorphisms (SNPs) are known to confer disease susceptibility and influence treatment response, we aimed to identify novel tripartite motif-containing 22 (TRIM22) SNPs that were associated with therapeutic efficacy in patients with CHB after PegIFNα treatment. Samples from 107 patients with CHB were genotyped using Asian Screening Array gene chips. The related mechanisms of SNPs screened were explored through both cell experiments and RNA sequence methods. TRIM22 was the most upregulated upon stimulation with PegIFNα. Specifically, the SNP rs10838543 CC genotype in TRIM22 was found to be associated with the positive response to PegIFNα treatment. The SNP rs10838543 CC genotype in TRIM22 was more stable and more robustly inhibited hepatitis B virus (HBV) replication in HepAD38 cells compared to the TT genotype. Mechanistically, we showed that the cytokine-cytokine receptor interaction signaling pathway was significantly upregulated in HepAD38 cells stably expressing the SNP rs10838543 CC genotype of TRIM22 compared to the TT genotype after PegIFNα treatment and that the SNP rs10838543 CC genotype in TRIM22 enhanced PegIFNα-induced anti-HBV activity by inducing the secretion of IFNL1, CCL3, and CCL5. The SNP rs10838543 CC genotype in TRIM22 increased the secretion of the cytokines IFNL1, CCL3, and CCL5 from hepatocytes by regulating the cytokine-cytokine receptor interaction signaling pathway and was positively correlated with the PegIFNα-induced treatment response in patients with CHB. Our findings suggest that genotyping patients with CHB for the SNP rs10838543 in TRIM22 may be a useful biomarker to help physicians identify patients who are most likely to benefit from PegIFNα treatment. IMPORTANCE Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.