Willem P. BrouwerHenry L.Y. ChanPietro LamperticoJinlin HouPisit TangkijvanichHendrik W. ReesinkWenhong ZhangAlessandra MangiaTawesak TanwandeeGiuseppe MontaltoKris SimonNecati OrmeciLiang ChenFehmi TabakFulya GunsarRobert FlisiakPeter FerenciMeral AkdoganFiliz AkyuzNattiya HirankarnLouis JansenVincent Wai Sun WongRoberta SoffrediniXieer LiangShalom ChenZwier M.A. GroothuisminkRosanna SantoroJerzy JaroszewiczResat OzarasKarin KozbialMayur BrahmaniaQing XieWatcharasak ChotiyaputtaQi XunMonika Pazgan-SimonErkin OztasElke VerheyNoé R. MontanariJian SunBettina E. HansenAndre BoonstraHarry L.A. JanssenBettina HansenHarry JanssenHeng ChiMilan SonneveldRob De KnegtHenry ChanVincent WongGrace WongPietro LamperticoMarta BorghiAlessandro LoglioJinlin HouJian SunXieer LiangPisit TangkijvanichNattiya HirankarnPimpayao SodsaiNatthaya ChuaypenHenk ReesinkWenhong ZhangShalom ChenAlessandra MangiaRosanna SantoroGuiseppe MontaltoKris SimonLiang ChenXi QunRobert FlisiakJerzy JaroszewiczPeter FerenciErkin OztasFiliz AkyuzJordan FeldSeham NoureldinSimin GuoQing XieShanghai Jiao Tong University School of MedicineIRCCS Casa Sollievo della SofferenzaErasmus MCUniversità degli Studi di MilanoChulalongkorn UniversitySlaski Uniwersytet Medyczny w KatowicachUniwersytet Medyczny w BialymstokuToronto General HospitalUniversità degli Studi di PalermoAnkara ÜniversitesiIstanbul Üniversitesi Tıp FakültesiMedizinische Universitat WienFaculty of Medicine, Siriraj Hospital, Mahidol UniversityFudan UniversityEge University Medical SchoolWroclaw Medical UniversityChinese University of Hong KongAmsterdam UMC - University of AmsterdamYuksek Ihsitas HospitalCerrahpasa Medical FacultySouthern Medical University2020-01-272020-01-272019-11-13Clinical Infectious Diseases. Vol.69, No.11 (2019), 1969-197915376591105848382-s2.0-85070654880https://repository.li.mahidol.ac.th/handle/20.500.14594/51310© 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.Mahidol UniversityMedicineArticleSCOPUS10.1093/cid/ciz084