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Clin Infect Dis. 2019 Feb 2. doi: 10.1093/cid/ciz084. [Epub ahead of print]
Genome Wide Association Study Identifies Genetic Variants Associated With Early And Sustained Response To (Peg)Interferon In Chronic Hepatitis B Patients: The GIANT-B Study.
Brouwer WP1, Chan HL2, Lampertico P3, Hou J4, Tangkijvanich P5, Reesink HW6, Zhang W7, Mangia A8, Tanwandee T9, Montalto G10, Simon K11, Ormeci N12, Chen L13, Tabak F14, Gunsar F15, Flisiak R16, Ferenci P17, Akdogan M18, Akyuz F19, Hirankarn N5, Jansen L6, Wong Wai-Sun V2, Soffredini R3, Liang X4, Chen S7, Groothuismink ZM1, Santoro R8, Jaroszewicz J16,20, Ozaras R14, Kozbial K17, Brahmania M21, Xie Q22, Chotiyaputta W9, Xun Q13, Pazgan-Simon M11, Oztas E18, Verhey E1, Montanari NR1, Sun J4, Hansen BE1, Boonstra A1, Janssen H1,20; GIANT-B Global Consortium.
Author information
1
Gastroenterology & Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands.
2
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
3
CRC "A. M. and A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, 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, Netherlands.
7
Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital "Fu Dan University", Shanghai, China.
8
IRCCS 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, Palermo, Italy.
11
Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Wroclaw, Poland.
12
University of Ankara, Medical School, Ankara, Turkey.
13
Shanghai Public Health Center "Fu Dan University", Shanghai, China.
14
Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul, Turkey.
15
Ege University Medical School, Izmir, Turkey.
16
Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland.
17
Medical University of Vienna, Vienna, Austria.
18
Yuksek Ihsitas Hospital, Ankara, Turkey.
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, ON, Canada.
22
Shanghai Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China.
Abstract
Background & aims:
(Peg)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 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 centres from Europe, Asia and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined HBeAg-loss with HBVDNA <2,000 IU/mL, or an HBVDNA <2,000 IU/mL for HBeAg-negative patients.
Results:
Of 1,144 patients, 1,058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% HBsAg-loss. GWAS analysis stratified by HBeAg-status, adjusted for age, gender and the 4 ancestry components identified PRELID2rs371991 (B=-0.74, 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. G3BP2rs3821977 (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 PBMC of healthy controls stimulated with IFNα and TLR8. After stimulation less production of IP-10 and IL-10 proteins and more production of IL-8 was 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 counselling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.
Clinicaltrials.gov number:
NCT01401400.
PMID:
30715261
DOI:
10.1093/cid/ciz084 |
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