基因组广泛关联研究确定与慢性乙型肝炎患者早期和持续应

StephenW

Clin Infect Dis. 2019 Feb 2. doi: 10.1093/cid/ciz084. [Epub ahead of print]
Genome Wide Association Study Identifies Genetic Variants Associated With Early And Sustained Response To (Peg)Interferon In Chronic Hepatitis B Patients: The GIANT-B Study.
Brouwer WP1, Chan HL2, Lampertico P3, Hou J4, Tangkijvanich P5, Reesink HW6, Zhang W7, Mangia A8, Tanwandee T9, Montalto G10, Simon K11, Ormeci N12, Chen L13, Tabak F14, Gunsar F15, Flisiak R16, Ferenci P17, Akdogan M18, Akyuz F19, Hirankarn N5, Jansen L6, Wong Wai-Sun V2, Soffredini R3, Liang X4, Chen S7, Groothuismink ZM1, Santoro R8, Jaroszewicz J16,20, Ozaras R14, Kozbial K17, Brahmania M21, Xie Q22, Chotiyaputta W9, Xun Q13, Pazgan-Simon M11, Oztas E18, Verhey E1, Montanari NR1, Sun J4, Hansen BE1, Boonstra A1, Janssen H1,20; GIANT-B Global Consortium.
Author information

1
    Gastroenterology & Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands.
2
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
3
    CRC "A. M. and A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
4
    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Dept of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
5
    Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
6
    Academic Medical Centre, Amsterdam, Netherlands.
7
    Clinical Center Hepatitis, Institute of Biomedical Science, Huashan hospital "Fu Dan University", Shanghai, China.
8
    IRCCS Casa Sollievo della Sofferenza, Foggia, Italy.
9
    Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
10
    Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.
11
    Wroclaw University of Medicine Department of Infectious Diseases and Hepatology, Wroclaw, Poland.
12
    University of Ankara, Medical School, Ankara, Turkey.
13
    Shanghai Public Health Center "Fu Dan University", Shanghai, China.
14
    Cerrahpasa Medical Faculty, Department of Infectious Diseases, Istanbul, Turkey.
15
    Ege University Medical School, Izmir, Turkey.
16
    Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland.
17
    Medical University of Vienna, Vienna, Austria.
18
    Yuksek Ihsitas Hospital, Ankara, Turkey.
19
    Istanbul Üniversitesi Istanbul Tip Fakültesi Hastanesi, Istanbul, Turkey.
20
    Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland.
21
    Liver Clinic, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
22
    Shanghai Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China.

Abstract
Background & aims:

(Peg)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 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 centres from Europe, Asia and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined HBeAg-loss with HBVDNA <2,000 IU/mL, or an HBVDNA <2,000 IU/mL for HBeAg-negative patients.
Results:

Of 1,144 patients, 1,058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% HBsAg-loss. GWAS analysis stratified by HBeAg-status, adjusted for age, gender and the 4 ancestry components identified PRELID2rs371991 (B=-0.74, 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. G3BP2rs3821977 (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 PBMC of healthy controls stimulated with IFNα and TLR8. After stimulation less production of IP-10 and IL-10 proteins and more production of IL-8 was 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 counselling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.
Clinicaltrials.gov number:

NCT01401400.

PMID:
    30715261
DOI:
    10.1093/cid/ciz084

StephenW

Clin Infect Dis。 2019年2月2日。土井：10.1093 / cid / ciz084。 [印刷前的电子版]
基因组广泛关联研究确定与慢性乙型肝炎患者早期和持续应答（Peg）干扰素相关的遗传变异：GIANT-B研究。
Brouwer WP1，Chan HL2，Lampertico P3，Hou J4，Tangkijvanich P5，Reesink HW6，张W7，Mangia A8，Tanwandee T9，Montalto G10，Simon K11，Ormeci N12，Chen L13，Tabak F14，Gunsar F15，Flisiak R16，Ferenci P17 ，Akdogan M18，Akyuz F19，Hirankarn N5，Jansen L6，Wong Wai-Sun V2，Soffredini R3，Liang X4，Chen S7，Groothuismink ZM1，Santoro R8，Jaroszewicz J16,20，Ozaras R14，Kozbial K17，Brahmania M21，Xie Q22 ，Chotiyaputta W9，Xun Q13，Pazgan-Simon M11，Oztas E18，Verhey E1，Montanari NR1，Sun J4，Hansen BE1，Boonstra A1，Janssen H1,20; GIANT-B Global Consortium。
作者信息

1
    荷兰鹿特丹鹿特丹伊拉斯谟医疗中心消化内科和肝病学。
2
    香港中文大学医学与治疗学系，香港，香港。
3
    CRC“A. M.和A. Migliavacca”肝病中心，消化内科和肝病学，FondazioneIRCCSCàGrandaOspedale Maggiore Policlinico，米兰大学，米兰，意大利。
4
    南方医科大学南方医院广东省病毒性肝炎重点实验室器官失效研究国家重点实验室，肝病科，传染病科，广州
五
    泰国曼谷朱拉隆功大学医学院。
6
    荷兰阿姆斯特丹学术医疗中心。
7
    临床中心肝炎，生物医学研究所，华山医院“复旦大学”，上海，中国。
8
    IRCCS Casa Sollievo della Sofferenza，Foggia，意大利。
9
    泰国曼谷玛希隆大学Siriraj医院医学系消化内科。
10
    意大利巴勒莫巴勒莫大学生物医学内科和专科。
11
    弗罗茨瓦夫医科大学传染病与肝病学系，波兰弗罗茨瓦夫。
12
    安卡拉大学，医学院，安卡拉，土耳其。
13
    上海市公共卫生中心“复旦大学”，中国上海。
14
    土耳其伊斯坦布尔传染病科Cerrahpasa医学院。
15
    埃格大学医学院，土耳其伊兹密尔。
16
    波兰比亚韦斯托克比亚韦斯托克医科大学传染病与肝病学系。
17
    维也纳医科大学，维也纳，奥地利。
18
    Yuksek Ihsitas医院，安卡拉，土耳其。
19
    伊斯坦布尔Üniversitesi伊斯坦布尔提示FakültesiHastanesi，伊斯坦布尔，土耳其。
20
    波兰卡托维兹西里西亚医科大学传染病与肝病学系。
21
    肝脏诊所，多伦多综合医院，大学健康网络，多伦多，ON，加拿大。
22
    上海交通大学医学院附属瑞金医院，上海

抽象
背景和目标：

（Peg）干扰素（（Peg）IFN）治疗导致少数慢性乙型肝炎（CHB）患者的反应。因此需要宿主遗传决定因素。
方法：

在该GWAS中，在来自欧洲，亚洲和北美的21个中心招募CHB患者，其在（Peg）IFN中治疗至少12周±核苷（t）ide类似物在随机试验中或作为标准治疗。 （Peg）IFN治疗后24周的反应定义为HBeAg消失，HBVDNA <2,000 IU / mL，或HBVDA <2,000 IU / mL，HBeAg阴性患者。
结果：

在1,144名患者中，1,058名（92％）患者被纳入GWAS分析。总共有282名（31％）患者获得了反应，4％HBsAg减少。根据HBeAg状态进行分层的GWAS分析，根据年龄，性别和4个血统成分进行调整，确定HBeAg阳性患者的PRELID2rs371991（B = -0.74，SE = 0.16，p = 3.44 * 10-6）。重要的是，PRELID2经过交叉验证，可用于HBeAg阴性患者的长期反应。 G3BP2rs3821977（B = 1.13，SE = 0.24，p = 2.46 * 10-6）与HBeAg阴性患者的反应相关。 G3BP2在干扰素途径中起作用，并且在用IFNα和TLR8刺激的健康对照的PBMC中进一步检查。刺激后，用G3BP2 G等位基因观察到IP-10和IL-10蛋白的产生减少，IL-8产生更多。
结论：

尽管未发现全基因组显着的命中，但目前的GWAS鉴定了与CHB中的（Peg）IFN应答相关的遗传变异。目前的研究结果可能为基因多态性指导的临床咨询铺平道路，无论是在（Peg）IFN和自然史中，还是可能用于新的免疫调节疗法。
Clinicaltrials.gov号码：

NCT01401400。

结论：
    30715261
DOI：
    10.1093 / CID / ciz084