The Role of ALPK1 in Inhibiting HBV Replication Facilitates the Identification of ALPK1 P660L Variant for Predicting PegIFNα Therapy Response.

Abstract

ALPK1 agonist has recently been reported to demonstrate anti-HBV efficacy via activating NF-κB signaling, which is crucial for maximizing interferon responses. Here, we investigated the impact of ALPK1 on HBV replication, and explored ALPK1 variants for predicting PegIFNα treatment response. The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out and their correlations with PegIFNα treatment response were assessed in 945 HBeAg-positive chronic hepatitis B (CHB) patients. We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFNα in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR, namely HBeAg seroconversion and HBV DNA level <3.3log10IU/ml) to PegIFNα treatment in CHB patients (P = 2.12 × 10-6). Moreover, a polygenic score (PGS) integrating ALPK1_rs35389530 and two additional genetic variants was further significantly associated with CR (Ptrend = 9.28 × 10-7), HBsAg level (Ptrend = 0.0002), and HBsAg loss (Ptrend = 0.025). The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1_rs35389530 and PGS are potential biomarkers to predict PegIFNα treatment response and may be utilized for optimizing CHB treatment.