Association of CASP10 rs13006529 with response to PEG-IFN-α-based therapy in chronic hepatitis B: Enhanced activity of caspase in HBV burden.

BACKGROUND & AIMS: Caspase-10 (CASP10) participates in death receptor-mediated apoptosis, but the relevance of the CASP10 coding variant rs13006529 (T > A; p.Leu522Ile) to PEG-IFN-α response in chronic hepatitis B (CHB) is unknown. We assessed this association and whether differential apoptotic activity explains variant-associated HBV burden. METHODS: rs13006529 was genotyped in 262 patients receiving PEG-IFN-α with or without nucleos(t)ide analogues. Allele and genotype frequencies were compared by χ2 tests; sustained virological response (SVR) was analyzed by univariable and multivariable logistic regression. HBV-infected HepG2-NTCP cells expressing empty vector or either CASP10 variant were compared; variant-expressing cells received vehicle or zVAD-fmk. Apoptosis was assessed by flow cytometry, caspase-3/7 activity, and Western blotting. HBV total RNA and pgRNA, intracellular DNA, cccDNA, and HBsAg/HBeAg were measured by RT-qPCR, qPCR, Southern blotting, and ELISA, respectively. RESULTS: The A allele was more frequent in patients without than with SVR (30.6% vs 17.1%; P = 0.002) and independently associated with lower odds of SVR (adjusted OR per A allele, 0.50; 95% CI, 0.27-0.86; P = 0.017). SVR rates were 36.9% in TT and 19.8% in AT/AA carriers (P = 0.003). Leu522-expressing cells showed greater apoptosis and lower HBV total RNA, pgRNA, intracellular DNA, and cccDNA than Ile522-expressing cells. zVAD-fmk attenuated the between-variant difference in apoptosis and partially narrowed the corresponding differences in HBV RNA and intracellular DNA. CONCLUSIONS: rs13006529 was independently associated with PEG-IFN-α response. Differential caspase-dependent apoptotic activity partly accounts for variant-associated HBV burden differences.