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
Authors: Brouwer Willem P , Chan Henry L Y , Lampertico Pietro , Hou Jinlin , Tangkijvanich Pisit , Reesink Hendrik W , Zhang Wenhong , Mangia Alessandra , Tanwandee Tawesak , Montalto Giuseppe , Simon Kris , Ormeci Necati , Chen Liang , Tabak Fehmi , Gunsar Fulya , Flisiak Robert , Ferenci Peter , Akdogan Meral , Akyuz Filiz , Hirankarn Nattiya , Jansen Louis , Wong Vincent Wai-Sun , Soffredini Roberta , Liang Xieer , Chen Shalom , Groothuismink Zwier M A , Santoro Rosanna , Jaroszewicz Jerzy , Ozaras Resat , Kozbial Karin , Brahmania Mayur , Xie Qing , Chotiyaputta Watcharasak , Xun Qi , Pazgan-Simon Monika , Oztas Erkin , Verhey Elke , Montanari Noé R , Sun Jian , Hansen Bettina E , Boonstra Andre , Janssen Harry L A ,   GIANT-B Global Consortium, 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 
Published: January 2019

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.