Dataset Information

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 ×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 IFN? 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.

SUBMITTER: Brouwer WP

PROVIDER: S-EPMC6853659 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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 WP Chan Henry L Y HLY Lampertico Pietro P Hou Jinlin J Tangkijvanich Pisit P Reesink Hendrik W HW Zhang Wenhong W Mangia Alessandra A Tanwandee Tawesak T Montalto Giuseppe G Simon Kris K Ormeci Necati N Chen Liang L Tabak Fehmi F Gunsar Fulya F Flisiak Robert R Ferenci Peter P Akdogan Meral M Akyuz Filiz F Hirankarn Nattiya N Jansen Louis L Wong Vincent Wai-Sun VW Soffredini Roberta R Liang Xieer X Chen Shalom S Groothuismink Zwier M A ZMA Santoro Rosanna R Jaroszewicz Jerzy J Ozaras Resat R Kozbial Karin K Brahmania Mayur M Xie Qing Q Chotiyaputta Watcharasak W Xun Qi Q Pazgan-Simon Monika M Oztas Erkin E Verhey Elke E Montanari Noé R NR Sun Jian J Hansen Bettina E BE Boonstra Andre A Janssen Harry L A HLA

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20191101 11

<h4>Background</h4>(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.<h4>Methods</h4>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 treatmen ...[more]

PMID: 30715261

Similar Datasets

Project description:BACKGROUND AND AIM:Hepatitis C virus (HCV) infection is a major health problem worldwide. Genotype-4 is the most common genotype in Saudi Arabia. The response to treatment with pegylated interferon-? combined with ribavirin in chronic HCV infection varies. This study aimed at investigating the pre- and on-treatment predictors of sustained virologic response (SVR) in patients with chronic hepatitis C (CHC) infection. PATIENTS AND METHODS:Clinical data of 48 patients with CHC treated with standard HCV antiviral combination therapy, between January 2005 and December 2010, at a Saudi University hospital, were retrospectively reviewed for age, sex, body mass index, liver enzymes, HCV-RNA viral load, liver biopsy, and response to treatment. The primary end point was SVR defined as undetectable HCV-RNA by polymerase chain reaction (PCR) 24 weeks after the end of treatment. Univariable logistic regression was used to explore the association between the different variables and SVR. These independent predictors of SVR were then analyzed with multivariable logistic regression analysis. RESULTS:Of the 48 treated patients, 25 (52%) were females and 27 (56%) were Saudi. The mean age was 43 years (43 ± 10 years). Twenty-four (50%) had genotype-4, and 26 (54%) had liver biopsy. The overall SVR rate was 75% (36/48) and was 83.3% (20/24) among genotype-4 patients. Baseline factors associated with SVR identified by univariate logistic regression were genotype-4 and early viral response (EVR), defined as a drop of ?2 log in serum HCV viral load after 12 weeks of initiation of combination therapy (P = 0.001). However, in stepwise regression analysis, the independent factor associated with the effect of antiviral therapy was genotype-4. When on-treatment variables were included, EVR (P = 0.003) and low baseline viral load (P = 0.048) were highly predictive of SVR. CONCLUSIONS:Of our HCV-treated patients, 75% had SVR. HCV genotype-4, EVR, and low baseline viral load were predictive of SVR.

Project description:AIM:To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-? (IFNL) polymorphisms. METHODS:This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 ?g pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS:A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION:The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets