Case Control Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2020; 26(12): 1329-1339
Published online Mar 28, 2020. doi: 10.3748/wjg.v26.i12.1329
Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population
Wan-Na Yang, Li-Li Pang, Ji-Yuan Zhou, Yuan-Wang Qiu, Liang Miao, Shou-Yun Wang, Xiang-Zhong Liu, Kang-An Tan, Wan-Wan Shi, Gui-Qiang Wang, Feng-Qin Hou
Wan-Na Yang, Kang-An Tan, Wan-Wan Shi, Gui-Qiang Wang, Feng-Qin Hou, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
Li-Li Pang, Department of Gastroenterology and Hematology, AEROSPACE 731 Hospital, Beijing 100074, China
Ji-Yuan Zhou, Department of Gastroenterology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
Yuan-Wang Qiu, Department of Liver Diseases, the Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi 214011, Jiangsu Province, China
Liang Miao, Shou-Yun Wang, Department of Liver Diseases, the Third Hospital of Qinhuangdao, Qinhuangdao 066001, Hebei Province, China
Xiang-Zhong Liu, Department of Liver Diseases, Yantai City Hospital for Infectious Diseases, Yantai 264001, Shandong Province, China
Gui-Qiang Wang, Feng-Qin Hou, Department of Infectious Diseases, Peking University International Hospital, Beijing 102206, China
Gui-Qiang Wang, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
Author contributions: Yang WN contributed to data collection, analyses, writing and revision; Pang LL, Zhou JY, Qiu YW, Miao L, Wang SY, Liu XZ, Tan KA and Shi WW contributed to data collection; Hou FQ and Wang GQ contributed to study design and critical revision of the manuscript for important intellectual content; Hou FQ had primary responsibility and all authors approved the final paper.
Supported by the National Natural Science Foundation of China, No. 81470849; and the China Mega-Project for Infectious Diseases, No. 2017ZX10203202.
Institutional review board statement: The study was approved by the Human Research Committee of Peking University First Hospital.
Informed consent statement: All patients gave informed consent.
Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Feng-Qin Hou, MD, Associate Professor, Chief Physician, Professor of Medicine, Department of Infectious Diseases, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing 100034, China. houfqys@139.com
Received: December 5, 2019
Peer-review started: December 5, 2019
First decision: January 12, 2020
Revised: February 7, 2020
Accepted: February 28, 2020
Article in press: February 28, 2020
Published online: March 28, 2020
Abstract
BACKGROUND

Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI.

AIM

To identify SNPs that indicate susceptibility to PM-DILI.

METHODS

We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant.

RESULTS

The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database.

CONCLUSION

rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Keywords: Drug-induced liver injury, Polygonum multiflorum, Single-nucleotide polymorphism, rs111686806, rs1055348, rs202047044, HLA-B*35:01

Core tip: We aimed to identify single-nucleotide polymorphisms that indicate susceptibility to Polygonum multiflorum-induced liver injury (PM-DILI). We successfully identified three single-nucleotide polymorphisms, rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene and rs202047044 in the HLA-DRB1 gene that were associated with PM-DILI. Of which, rs1055348 had the strongest effect and was a specific risk factor for PM-DILI. We also validated the association between HLA-B*35:01 and PM-DILI. Furthermore, we analyzed the correlation between rs1055348 and HLA-B*35:01. With 100% sensitivity and > 95% specificity, rs1055348 may serve as a tag for HLA-B*35:01 and an alternative predictive biomarker of PM-DILI.