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
Author:
Brouwer Willem P1ORCID, Chan Henry L Y2, Lampertico Pietro3, Hou Jinlin4, Tangkijvanich Pisit5, Reesink Hendrik W6, Zhang Wenhong7, Mangia Alessandra8, Tanwandee Tawesak9, Montalto Giuseppe10, Simon Kris11, Ormeci Necati12, Chen Liang13, Tabak Fehmi14, Gunsar Fulya15, Flisiak Robert16, Ferenci Peter17, Akdogan Meral18, Akyuz Filiz19, Hirankarn Nattiya5, Jansen Louis6, Wong Vincent Wai-Sun2, Soffredini Roberta3, Liang Xieer4, Chen Shalom7, Groothuismink Zwier M A1, Santoro Rosanna8, Jaroszewicz Jerzy1620, Ozaras Resat14, Kozbial Karin17, Brahmania Mayur21, Xie Qing22, Chotiyaputta Watcharasak9, Xun Qi13, Pazgan-Simon Monika11, Oztas Erkin18, Verhey Elke1, Montanari Noé R1, Sun Jian4, Hansen Bettina E1, Boonstra Andre1, Janssen Harry L A121, Brouwer Willem Pieter, Hansen Bettina, Verhey Elke, Boonstra Andre, Janssen Harry, Chi Heng, Sonneveld Milan, Montanari Noe Rico, de Knegt Rob, Chan Henry, Wong Vincent, Wong Grace, Lampertico Pietro, Borghi Marta, Loglio Alessandro, Soffredini Roberta, Hou Jinlin, Sun Jian, Liang Xieer, Tangkijvanich Pisit, Hirankarn Nattiya, Sodsai Pimpayao, Chuaypen Natthaya, Reesink Henk, Jansen Louis, Zhang Wenhong, Chen Shalom, Mangia Alessandra, Santoro Rosanna, Tanwandee Tawesak, Chotiyaputta Watcharasak, Montalto Guiseppe, Simon Kris, Pazgan-Simon Monika, Ormeci Necati, Chen Liang, Qun Xi, Tabak Fehmi, Gunsar Fulya, Flisiak Robert, Jaroszewicz Jerzy, Ferenci Peter, Kozbial Karin, Akdogan Meral, Oztas Erkin, Akyuz Filiz, Janssen Harry, Brahmania Mayur, Feld Jordan, Noureldin Seham, Guo Simin, Xie Qing,
Affiliation:
1. Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands 2. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy 3. Centro di riferimento per la diagnosi e lo studio delle malattie del fegato e delle vie biliari “Angela Maria ed Antonio Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy 4. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China 5. Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 6. Academic Medical Centre, Amsterdam, The Netherlands 7. Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital “Fu Dan University,” Shanghai, China 8. Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica Casa Sollievo della Sofferenza, Foggia, Italy 9. Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 10. Biomedical Department of Internal Medicine and Specialties, University of Palermo, Italy 11. Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Poland 12. University of Ankara, Medical School, Turkey 13. Shanghai Public Health Center “Fu Dan University,” China 14. Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul 15. Ege University Medical School, Izmir, Turkey 16. Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Poland 17. Medical University of Vienna, Austria 18. Yuksek Ihsitas Hospital, Ankara 19. Istanbul Üniversitesi Istanbul Tip Fakültesi Hastanesi, Istanbul, Turkey 20. Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland 21. Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Canada 22. Shanghai Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China
Abstract
AbstractBackground(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.MethodsIn 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.ResultsOf 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.ConclusionsAlthough 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 RegistationNCT01401400.
Funder
Merck Sharpe & Dohme Foundation for Liver and Gastrointestinal Research
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Microbiology (medical)
Cited by
15 articles.
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