Publication:
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

Issued Date

2019-11-13

Resource Type

Article

ISSN

15376591
10584838

DOI

10.1093/cid/ciz084

Other identifier(s)

2-s2.0-85070654880

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Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Clinical Infectious Diseases. Vol.69, No.11 (2019), 1969-1979

Suggested Citation

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 Akyuz, Nattiya 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, Bettina Hansen, Harry Janssen, Heng Chi, Milan Sonneveld, Rob De Knegt, Henry Chan, Vincent Wong, Grace Wong, Pietro Lampertico, Marta Borghi, Alessandro Loglio, Jinlin Hou, Jian Sun, Xieer Liang, Pisit Tangkijvanich, Nattiya Hirankarn, Pimpayao Sodsai, Natthaya Chuaypen, Henk Reesink, Wenhong Zhang, Shalom Chen, Alessandra Mangia, Rosanna Santoro, Guiseppe Montalto, Kris Simon, Liang Chen, Xi Qun, Robert Flisiak, Jerzy Jaroszewicz, Peter Ferenci, Erkin Oztas, Filiz Akyuz, Jordan Feld, Seham Noureldin, Simin Guo, Qing Xie 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. Vol.69, No.11 (2019), 1969-1979. doi:10.1093/cid/ciz084 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/51310

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Title

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(s)

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 Akyuz
 Nattiya 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
 Bettina Hansen
 Harry Janssen
 Heng Chi
 Milan Sonneveld
 Rob De Knegt
 Henry Chan
 Vincent Wong
 Grace Wong
 Pietro Lampertico
 Marta Borghi
 Alessandro Loglio
 Jinlin Hou
 Jian Sun
 Xieer Liang
 Pisit Tangkijvanich
 Nattiya Hirankarn
 Pimpayao Sodsai
 Natthaya Chuaypen
 Henk Reesink
 Wenhong Zhang
 Shalom Chen
 Alessandra Mangia
 Rosanna Santoro
 Guiseppe Montalto
 Kris Simon
 Liang Chen
 Xi Qun
 Robert Flisiak
 Jerzy Jaroszewicz
 Peter Ferenci
 Erkin Oztas
 Filiz Akyuz
 Jordan Feld
 Seham Noureldin
 Simin Guo
 Qing Xie

Other Contributor(s)

Shanghai Jiao Tong University School of Medicine
 IRCCS Casa Sollievo della Sofferenza
 Erasmus MC
 Università degli Studi di Milano
 Chulalongkorn University
 Slaski Uniwersytet Medyczny w Katowicach
 Uniwersytet Medyczny w Bialymstoku
 Toronto General Hospital
 Università degli Studi di Palermo
 Ankara Üniversitesi
 Istanbul Üniversitesi Tıp Fakültesi
 Medizinische Universitat Wien
 Faculty of Medicine, Siriraj Hospital, Mahidol University
 Fudan University
 Ege University Medical School
 Wroclaw Medical University
 Chinese University of Hong Kong
 Amsterdam UMC - University of Amsterdam
 Yuksek Ihsitas Hospital
 Cerrahpasa Medical Faculty
 Southern Medical University

Abstract

© 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. 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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/51310

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Scopus 2019