A genetic variant of CXCR4 predicts pegylated interferon-alpha treatment response in HBeAg-positive chronic hepatitis B patients

Abstract

<p>Chemokine receptor 4 (CXCR4) plays a vital role in immunoregulation during hepatitis B virus (HBV) infection. This study aimed to screen single-nucleotide polymorphisms (SNPs) of <em>CXCR4</em> for predicting pegylated interferon-alpha (PegIFNα) therapy response in chronic hepatitis B (CHB) patients. This retrospective cohort study enrolled a total of 945 CHB patients in two cohorts (Cohort 1, <em>n</em> = 238; Cohort 2, <em>n</em> = 707), and all the patients were hepatitis B e antigen (HBeAg)-positive and treated with PegIFNα for 48 weeks and followed up for 24 weeks. Twenty-two tag SNPs were selected in <em>CXCR4</em> and its flanking region. A polygenic score (PGS) was utilized to evaluate the cumulative effect of multiple SNPs. The relationships between <em>CXCR4</em> SNPs and PGS and PegIFNα treatment response were explored in the two cohorts. Among the 22 candidate SNPs of <em>CXCR4</em>, rs28367495 (T > C) was significantly linked to PegIFNα treatment response in both cohorts. In patients with more number of rs28367495 C allele, a higher rate of combined response (CR, defined as HBeAg seroconversion and HBV DNA level < 3.3 log₁₀ IU/mL; <em>P</em> = 1.51 × 10⁻⁴), a lower mean hepatitis B surface antigen (HBsAg) level (<em>P</em> = 4.76 × 10⁻⁴), and a higher mean HBsAg decline (<em>P</em> = 3.88 × 10⁻⁴) at Week 72 were achieved. Moreover, a PGS integrating <em>CXCR4</em>_rs28367495 and five previously reported SNPs was strongly correlated with CR (<em>P</em> = 1.26 × 10⁻¹³), HBsAg level (<em>P</em> = 4.90 × 10⁻⁴), and HBsAg decline (<em>P</em> = 0.005) in all the patients of the two cohorts. <em>CXCR4</em>_rs28367495 is a promising indicator for predicting the responsiveness to PegIFNα treatment for HBeAg-positive CHB patients. The new PGS may further improve the prediction performance.</p>