A Genetic Variant of TLR6 Predicts HBsAg Decline After Pegylated Interferon‐Alpha Treatment in HBeAg‐Positive Chronic Hepatitis B

ABSTRACT Although toll‐like receptor 6 ( TLR6 ) plays an important role in innate immunity and host antiviral responses, its impact on pegylated interferon‐alpha (PegIFNα) treatment efficacy in chronic hepatitis B (CHB) remains unclear. We aimed to investigate whether genetic variations of TLR6 are associated with the response to PegIFNα treatment. This study included 945 HBeAg‐positive CHB patients treated with PegIFNα for at least 48 weeks and followed for 24 weeks from two multicenter phase IV trials (Cohort 1, n = 238; Cohort 2, n = 707). Across the TLR6 gene, 13 tag‐SNPs were selected. Furthermore, a polygenic score (PGS) was developed by incorporating the newly identified variant of TLR6 and two previously reported SNPs ( CD55 _rs28371597 and CXCR4 _rs28367495). Both TLR6 tag‐SNPs and PGS were tested their associations with treatment efficacy. Among the 13 tag‐SNPs, TLR6 _rs7696175 ( C > T ) was identified as the most significantly associated variant with HBsAg decline at week 72 in both cohorts. The T allele of TLR6 _rs7696175 was significantly associated with greater HBsAg decline, especially higher rates of decline ≥ 1 log 10 IU/mL and ≥ 2 log 10 IU/mL at week 72 (Cohort 1 + 2: p ≤ 0.001 for all associations). Moreover, the PGS integrating TLR6 _rs7696175 and two previously reported SNPs significantly improved prediction accuracy for HBsAg decline at week 72 (Cohort 1 + 2: p < 0.001 for all comparisons) and outperformed single SNPs. Overall, this study identifies TLR6 _rs7696175 as a novel genetic biomarker and demonstrates the superiority of a compact PGS for predicting HBsAg decline in PegIFNα‐treated CHB patients, facilitating personalized treatment for CHB.