A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B

Jing Li; Haitao Chen; Jiaxuan Chen; Bin Zhou; Jinlin Hou; De-Ke Jiang

doi:10.2147/PGPM.S337962

A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B

Pharmgenomics Pers Med. 2021 Nov 23:14:1505-1515. doi: 10.2147/PGPM.S337962. eCollection 2021.

Authors

Jing Li^#¹, Haitao Chen^#^{1

2}, Jiaxuan Chen^#¹, Bin Zhou¹, Jinlin Hou¹, De-Ke Jiang¹

Affiliations

¹ State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
² School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Granulysin (GNLY) is a cytotoxic granule that has been reported to have various antimicrobial activities. We evaluated the association between a missense variant in GNLY (rs11127) and treatment efficacy of pegylated interferon-alpha (PegIFNα) or nucleos(t)ide analogs (NUCs) in patients with chronic hepatitis B (CHB).

Patients and methods: We included a total of 1823 patients with hepatitis B e antigen (HBeAg)-positive CHB (954 patients treated with PegIFNα and 869 patients treated with NUCs) in four Phase IV multicenter randomized controlled trials. The association of the GNLY rs11127 genotype with the combined response (CR), defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA level <2000 IU/mL was evaluated. A polygenic score (PGS) was constructed to evaluate the cumulative effect of multiple single-nucleotide polymorphisms (SNPs), including rs11127 and several other SNPs, STAT4 rs7574865, CFB rs12614, and CD55 rs28371597, which were reported to be associated with CR.

Results: GNLY rs11127 was significantly associated with CR in patients treated with PegIFNα. The CR rate in patients with the rs11127 CC genotype was higher than that with the CT or TT genotype (40.98% vs 30.34% or 27.09%, P = 0.003). Furthermore, a PGS integrating GNLY rs11127 and three other SNPs was significantly associated with CR in PegIFNα-treated patients (P < 0.001). However, no significant correlation was found between GNLY rs11127 and CR in NUCs-treated patients.

Conclusion: GNLY rs11127 is an independent biomarker for predicting the response to PegIFNα therapy in HBeAg-positive CHB patients. Furthermore, the PGS, including GNLY rs11127, provides new insights for individualized treatment in clinical practice.

Keywords: GNLY; PegIFNα treatment; chronic hepatitis B; polygenic score; rs11127.

Grants and funding

This study was supported by the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131), the National Science and Technology Major Project (No. 2017ZX10202202 and 2018ZX10301202), the General Programs from the National Natural Science Foundation of China (No. 81472618, 81670535, 81802828 and 81802833), the General Program from the Natural Science Foundation of Guangdong Province (No. 2019A1515011423), the Key-Area Research and Development Program of Guangdong Province (No. 2019B020227004), the Innovative Research Team Project of Guangxi Province (No. 2017GXNSFGA198002), the Dean Fund of Nanfang Hospital, Southern Medical University (No. 2018Z005), the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital, and the Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (No. 2017J001).