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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
59 Pages Posted: 20 Sep 2018
More...Abstract
Background & Aims: (Peg)interferon ((Peg)IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. The identification of host genetic determinants of response to (Peg)IFN in CHB patients is therefore in demand.
Methods: In this investigator-initiated multicentre 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 centres from Europe, Asia and North America. The GWAS cohort included 1,144 patients. Primary response at 24 weeks after (PEG)IFN treatment was defined as combined HBeAg loss with HBV DNA <2,000 IU/mL, or an HBV DNA <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 a primary response and 4% HBsAg loss. GWAS analysis stratified by HBeAg status, adjusted for age, gender and the 4 ancestry principal components identified PRELID2 rs371991 (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 HBeAgnegative 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 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.
Clinical Trial Number: clinicaltrials.gov, identifier NCT01401400.
Funding Statement: Financial support for this study was provided by Merck Sharpe & Dohme (MSD) Asia, the Foundation for Liver and Gastrointestinal Research (SLO) in Rotterdam, The Netherlands and by the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 050-060-452. Financial support for the original (randomized) trials are described elsewhere.(7, 8, 10, 12-20, 22) The funding sources did not have any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication.
Declaration of Interests: H.L.Y. Chan is a consultant of AbbVie, Arbutus, Aptorum, Bristol Myers Squibb, Gilead Sciences, GRAIL, Intellia, MedImmune, Roche, and VIR Biotechnology; and is a speaker for AbbVie, Gilead Sciences, and Roche. P. Lampertico: speakers’ bureau and or advisory board of Bristol-Myers Squibb, Roche, Gilead, GlaxoSmithKline, MSD, Abbvie, Janssen. H.L.A. Janssen received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche and Merck. A. Boonstra received grants from Roche, Gilead Sciences, Fujirebio, and Janssen and is a consultant for Gilead Sciences. J Hou is a consultant for AbbVie, Arbutus, Bristol Myers Squibb, Gilead Sciences, Johnson &Johnson, Roche and received grants from Bristol Myers Squibb, GSK and Johnson &Johnson. P.Ferenci consultant for Roche, Abbvie, BMS, Gilead, MSD. V.W.S. Wong has served as a consultant for AbbVie, Allergan, Center for Outcomes Research in Liver Diseases, Gilead Sciences, Janssen, Perspectum Diagnostics, Pfizer and TARGET-NASH; and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck. J. Jaroszewicz is a consultant for AbbVie, BMS, Gilead and recived grants form AbbVie, BMS, Gilead, MSD and Roche. The other authors have nothing to disclose.
Ethics Approval Statement: The study was conducted in agreement with the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice. The study was approved by the ethics committee of each participating centre. All patients gave written informed consent according to standards of the local ethics committees at each of the participating centres.
Keywords: Peginterferon, Chronic Hepatitis B, Response, GWAS, Genetics
Suggested Citation: Suggested Citation