Abstract
Seroconversion of hepatitis B virus (HBV) e-antigen (HBeAg) is a critical but often-missed therapeutic goal in standard antiviral treatments. An extreme-phenotype genome-wide association study was performed, comparing untreated spontaneous recoverers (with seroconversion of HBV surface antigen) versus entecavir-treated patients failing to achieve HBeAg seroconversion. A single-nucleotide-polymorphism rs2132039 on the UGT2B28 gene, alongside an adjacent copy number polymorphism (CNP605), manifested the strongest clinical associations (P = 3.4 × 10−8 and 0.001, respectively). Multivariate analysis showed that rs2132039-TT genotypes, but not CNP605 copy numbers, remained associated to spontaneous recoverers (P = 0.009). The clinical association of rs2132039 was validated successfully in an independent cohort (n = 302; P = 0.002). Longitudinal case-only analyses revealed that the rs2132039-TT genotype predicted shorter time-to-HBeAg-seroconversion in all antiviral-treated patients (n = 380, P = 0.012), as well as the peginterferon-treated subgroup (n = 123; P = 0.024, Hazard ratio [HR] = 2.104, Confidence interval [CI] = 1.105–4.007). In the entecavir-treated subgroup, the predictive effect was restricted by pretreatment alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with effective prediction observed in patients with ALT < 200 IU/ml and ALT/AST ratio <2 (n = 132; P = 0.013, HR = 10.538, CI = 1.420–78.196).
Highlights
Rs2132039 on the UGT2B28 gene, alongside an adjacent copy number polymorphism (CNP605), manifested the strongest clinical associations (P = 3.4 × 10−8 and 0.001, respectively)
We searched for associated genomic biomarkers, first by a cross-sectional genome-wide association study (GWAS) with independent cohort validation, followed by longitudinal case-only analyses of patients treated by peginterferon or entecavir, the first-line immune modulator and nucleos(t)ide analog respectively in Taiwan
The extreme-phenotype GWAS was performed on 27 unrelated patients who did not achieve HBV e-antigen (HBeAg)-seroclearance after two years of continuous entecavir treatment, and 30 spontaneous recoverers who were negative for serum HBV surface antigen (HBsAg) but positive for anti-HBsAg and anti-hepatitis B core antigen (HBcAg) antibodies, an evidence of spontaneous recovery from past hepatitis B virus (HBV) infection
Summary
Subsequent validation and longitudinal studies were performed on 110 spontaneous recoverers, 326 carriers in the inactive residual clinical phase (post HBeAg seroconversion, normal ALT), and 380 patients in the immune-clearance phase who were treated between years 2001 and 2013. A significant difference of UGT2B28 genotype distribution was found between patients with or without HBeAg seroconversion 200 days after the start of entecavir treatment (Fisher’s exact test, P = 0.033, N = 257). Five factors, including age (P = 0.002), cirrhosis (P = 0.003), ALT/AST ratio (P = 0.034), rs2132039 genotype (P = 0.012) and treatment methods (P < 0.001), were significantly associated to time-to-HBeAg seroconversion in the univariate analysis (Table 3).
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