Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study

GIANT-B Global Consortium , Willem P Brouwer, Henry L Y Chan, Pietro Lampertico, Jinlin Hou, Pisit Tangkijvanich, Hendrik W Reesink, Wenhong Zhang, Alessandra Mangia, Tawesak Tanwandee, Giuseppe Montalto, Kris Simon, Necati Ormeci, Liang Chen, Fehmi Tabak, Fulya Gunsar, Robert Flisiak, Peter Ferenci, Meral Akdogan, Filiz AkyuzNattiya Hirankarn, Louis Jansen, Vincent Wai-Sun Wong, Roberta Soffredini, Xieer Liang, Shalom Chen, Zwier M A Groothuismink, Rosanna Santoro, Jerzy Jaroszewicz, Resat Ozaras, Karin Kozbial, Mayur Brahmania, Qing Xie, Watcharasak Chotiyaputta, Qi Xun, Monika Pazgan-Simon, Erkin Oztas, Elke Verhey, Noé R Montanari, Jian Sun, Bettina E Hansen, Andre Boonstra, Harry L A Janssen

Research output: Contribution to journalArticle

Abstract

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand.

METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients.

RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele.

CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.

CLINICAL TRIALS REGISTATION: NCT01401400.

Original languageEnglish
Pages (from-to)1969-1979
Number of pages11
JournalClinical infectious diseases : an official publication of the Infectious Diseases Society of America
Volume69
Issue number11
DOIs
Publication statusPublished - Nov 13 2019

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    GIANT-B Global Consortium , Brouwer, W. P., Chan, H. L. Y., Lampertico, P., Hou, J., Tangkijvanich, P., Reesink, H. W., Zhang, W., Mangia, A., Tanwandee, T., Montalto, G., Simon, K., Ormeci, N., Chen, L., Tabak, F., Gunsar, F., Flisiak, R., Ferenci, P., Akdogan, M., ... Janssen, H. L. A. (2019). Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 69(11), 1969-1979. https://doi.org/10.1093/cid/ciz084