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

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 log₁₀ IU/mL and ≥ 2 log₁₀ 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.