全基因组关联研究确定慢性乙型肝炎患者对（聚乙二醇化）干扰素早期和持续应答相关的基因变异：GIANT-B研究。
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.
作者信息
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
机构信息
Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Italy.
出版信息
Clin Infect Dis. 2019 Nov 13;69(11):1969-1979. doi: 10.1093/cid/ciz084.
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.
背景
（聚乙二醇化）干扰素（[Peg]IFN）治疗仅能使少数慢性乙型肝炎（CHB）患者产生应答。因此，需要确定决定应答的宿主遗传因素。
方法
在这项全基因组关联研究（GWAS）中，从欧洲、亚洲和北美的21个中心招募了在随机试验中或作为标准治疗接受（Peg）IFN治疗至少12周±核苷（酸）类似物的CHB患者。（Peg）IFN治疗24周后的应答定义为乙肝e抗原（HBeAg）转阴且乙肝病毒（HBV）DNA<2000 IU/mL，或HBeAg阴性患者的HBV DNA<2000 IU/mL。
结果
1144例患者中，1058例（92%）纳入GWAS分析。共有282例（31%）患者获得应答，4%患者乙肝表面抗原（HBsAg）转阴。GWAS分析按HBeAg状态分层，校正年龄、性别和4个祖先成分后，在HBeAg阳性患者中鉴定出PRELID2 rs371991（B=-0.74，标准误[SE]=0.16，P=3.44×10-6）。重要的是，PRELID2在HBeAg阴性患者的长期应答中得到了交叉验证。G3BP2 rs3821977（B=1.13，SE=0.24，P=2.46×10-6）与HBeAg阴性患者的应答相关。G3BP2在干扰素途径中起作用，并在IFNα和TLR8刺激的健康对照外周血单个核细胞中进一步研究。刺激后，携带G3BP2 G等位基因的细胞中IP-10和白细胞介素（IL）-10蛋白产生减少，IL-8产生增加。
结论
虽然未发现全基因组显著关联信号，但当前的GWAS鉴定出了与CHB患者（Peg）IFN应答相关的遗传变异。目前的研究结果可为基因多态性指导的临床咨询铺平道路，无论是在（Peg）IFN治疗还是自然病程中，也可能为新的免疫调节疗法提供依据。
临床试验注册号
NCT01401400。
Zotero 插件