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

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; Heng Chi; Milan Sonneveld; Rob De Knegt; Grace Wong; Marta Borghi; Alessandro Loglio; Pimpayao Sodsai; Natthaya Chuaypen; Xi Qun; Jordan Feld; Seham Noureldin; Simin Guo

doi:10.1093/cid/ciz084

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

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, Heng Chi, Milan Sonneveld, Rob De Knegt, Grace Wong, Marta Borghi, Alessandro Loglio, Pimpayao Sodsai, Natthaya Chuaypen, Xi Qun, Jordan Feld, Seham Noureldin, Simin Guo

Department of Medicine

Erasmus Medical Center
Chinese University of Hong Kong
University of Milan
Southern Medical University
Chulalongkorn University
Amsterdam University Medical Centers
Fudan University
Department of Medical Sciences
University of Palermo
Wroclaw Medical University
Ankara University
Istanbul University
Ege University Medical School
Medical University of Bialystok
Medical University of Vienna
Yuksek Ihsitas Hospital
Medical University of Silesia
Toronto General Hospital
Shanghai Jiao Tong University School of Medicine

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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 language	English
Pages (from-to)	1969-1979
Number of pages	11
Journal	Clinical Infectious Diseases
Volume	69
Issue number	11
DOIs	https://doi.org/10.1093/cid/ciz084
Publication status	Published - 13 Nov 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

GWAS
chronic hepatitis B
genetics
peginterferon
response

Access to Document

10.1093/cid/ciz084

Cite this

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., Akyuz, F., ... Guo, S. (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, 69(11), 1969-1979. https://doi.org/10.1093/cid/ciz084

@article{f58de0fcd2df4473879f9fe07671e3f3,

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",

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 {\texttimes}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 {\texttimes} 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.",

keywords = "GWAS, chronic hepatitis B, genetics, peginterferon, response",

author = "Brouwer, \{Willem P.\} and Chan, \{Henry L.Y.\} and Pietro Lampertico and Jinlin Hou and Pisit Tangkijvanich and Reesink, \{Hendrik W.\} and Wenhong Zhang and Alessandra Mangia and Tawesak Tanwandee and Giuseppe Montalto and Kris Simon and Necati Ormeci and Liang Chen and Fehmi Tabak and Fulya Gunsar and Robert Flisiak and Peter Ferenci and Meral Akdogan and Filiz Akyuz and Nattiya Hirankarn and Louis Jansen and Wong, \{Vincent Wai Sun\} and Roberta Soffredini and Xieer Liang and Shalom Chen and Groothuismink, \{Zwier M.A.\} and Rosanna Santoro and Jerzy Jaroszewicz and Resat Ozaras and Karin Kozbial and Mayur Brahmania and Qing Xie and Watcharasak Chotiyaputta and Qi Xun and Monika Pazgan-Simon and Erkin Oztas and Elke Verhey and Montanari, \{No{\'e} R.\} and Jian Sun and Hansen, \{Bettina E.\} and Andre Boonstra and Janssen, \{Harry L.A.\} and Heng Chi and Milan Sonneveld and \{De Knegt\}, Rob and Grace Wong and Marta Borghi and Alessandro Loglio and Pimpayao Sodsai and Natthaya Chuaypen and Xi Qun and Jordan Feld and Seham Noureldin and Simin Guo",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.",

year = "2019",

month = nov,

day = "13",

doi = "10.1093/cid/ciz084",

language = "English",

volume = "69",

pages = "1969--1979",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "11",

}

Brouwer, WP, Chan, HLY, Lampertico, P, Hou, J, Tangkijvanich, P, Reesink, HW, Zhang, W, Mangia, A, Tanwandee, T, Montalto, G, Simon, K, Ormeci, N, Chen, L, Tabak, F, Gunsar, F, Flisiak, R, Ferenci, P, Akdogan, M, Akyuz, F, Hirankarn, N, Jansen, L, Wong, VWS, Soffredini, R, Liang, X, Chen, S, Groothuismink, ZMA, Santoro, R, Jaroszewicz, J, Ozaras, R, Kozbial, K, Brahmania, M, Xie, Q, Chotiyaputta, W, Xun, Q, Pazgan-Simon, M, Oztas, E, Verhey, E, Montanari, NR, Sun, J, Hansen, BE, Boonstra, A, Janssen, HLA, Chi, H, Sonneveld, M, De Knegt, R, Wong, G, Borghi, M, Loglio, A, Sodsai, P, Chuaypen, N, Qun, X, Feld, J, Noureldin, S & Guo, S 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, vol. 69, no. 11, pp. 1969-1979. https://doi.org/10.1093/cid/ciz084

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. / Brouwer, Willem P.; Chan, Henry L.Y.; Lampertico, Pietro et al.
In: Clinical Infectious Diseases, Vol. 69, No. 11, 13.11.2019, p. 1969-1979.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genome-wide Association Study Identifies Genetic Variants Associated with Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients

T2 - The GIANT-B Study

AU - Brouwer, Willem P.

AU - Chan, Henry L.Y.

AU - Lampertico, Pietro

AU - Hou, Jinlin

AU - Tangkijvanich, Pisit

AU - Reesink, Hendrik W.

AU - Zhang, Wenhong

AU - Mangia, Alessandra

AU - Tanwandee, Tawesak

AU - Montalto, Giuseppe

AU - Simon, Kris

AU - Ormeci, Necati

AU - Chen, Liang

AU - Tabak, Fehmi

AU - Gunsar, Fulya

AU - Flisiak, Robert

AU - Ferenci, Peter

AU - Akdogan, Meral

AU - Akyuz, Filiz

AU - Hirankarn, Nattiya

AU - Jansen, Louis

AU - Wong, Vincent Wai Sun

AU - Soffredini, Roberta

AU - Liang, Xieer

AU - Chen, Shalom

AU - Groothuismink, Zwier M.A.

AU - Santoro, Rosanna

AU - Jaroszewicz, Jerzy

AU - Ozaras, Resat

AU - Kozbial, Karin

AU - Brahmania, Mayur

AU - Xie, Qing

AU - Chotiyaputta, Watcharasak

AU - Xun, Qi

AU - Pazgan-Simon, Monika

AU - Oztas, Erkin

AU - Verhey, Elke

AU - Montanari, Noé R.

AU - Sun, Jian

AU - Hansen, Bettina E.

AU - Boonstra, Andre

AU - Janssen, Harry L.A.

AU - Chi, Heng

AU - Sonneveld, Milan

AU - De Knegt, Rob

AU - Wong, Grace

AU - Borghi, Marta

AU - Loglio, Alessandro

AU - Sodsai, Pimpayao

AU - Chuaypen, Natthaya

AU - Qun, Xi

AU - Feld, Jordan

AU - Noureldin, Seham

AU - Guo, Simin

PY - 2019/11/13

Y1 - 2019/11/13

N2 - 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.

AB - 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.

KW - GWAS

KW - chronic hepatitis B

KW - genetics

KW - peginterferon

KW - response

UR - https://www.scopus.com/pages/publications/85070654880

U2 - 10.1093/cid/ciz084

DO - 10.1093/cid/ciz084

M3 - Article

C2 - 30715261

AN - SCOPUS:85070654880

SN - 1058-4838

VL - 69

SP - 1969

EP - 1979

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 11

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this