HLA基因多态性与药物性肝损伤的关系

王露媛; 姜敏杰; 高普均

doi:10.3969/j.issn.1001-5256.2021.02.048

HLA基因多态性与药物性肝损伤的关系

DOI: 10.3969/j.issn.1001-5256.2021.02.048

吉林大学第一医院肝胆胰内科，长春 130021

基金项目:

“艾滋病和病毒性肝炎等重大传染病防治”国家科技重大专项 (2017ZX10202202);

“艾滋病和病毒性肝炎等重大传染病防治”国家科技重大专项 (2018ZX10302206);

“艾滋病和病毒性肝炎等重大传染病防治”国家科技重大专项 (2018ZX10723203);

国家重点研发计划“精准医学研究”专项 (2017YFC0908103);

吉林省自然科学基金 (2018SCZWSZX-003);

吉林省自然科学基金 (JLSCZD2019-008);

吉林大学高层次创新团队建设项目 (2017TD-08);

中央高校基本科研业务费专项资金

作者贡献声明：王露媛、高普均负责拟定写作思路；王露媛、姜敏杰负责检索文献，资料分析，参与收集数据；王露媛负责撰写文章；高普均负责指导撰写文章并最后定稿。

详细信息

作者简介:
王露媛(1993—)，男，主要从事肝脏疾病的临床研究

通信作者:
高普均，gpj0411@163.com

中图分类号: R575
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出版历程
- 收稿日期: 2020-08-08
- 录用日期: 2020-10-19
- 出版日期: 2021-02-20

Association between human leukocyte antigen gene polymorphism and drug-induced liver injury

Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, China

Research funding:

(2017ZX10202202);

(2018ZX10302206);

(2018ZX10723203);

(2017YFC0908103);

(2018SCZWSZX-003);

(JLSCZD2019-008);

(2017TD-08);

摘要

摘要: 药物性肝损伤是临床常见的药物不良反应之一，其临床诊治极为困难，且易发展成急性肝衰竭。相关药物基因组学研究已发现人类白细胞抗原(HLA)基因与药物性肝损伤之间有很强的遗传相关性。综述了药物性肝损伤的HLA基因多态性研究进展，以期揭示免疫因素在药物性肝损伤发生机制中的作用，发现相应基因生物标志物，提高临床用药的安全性。
- 化学性与药物性肝损伤 /
- HLA抗原 /
- 多态性, 单核苷酸
Abstract: Drug-induced liver injury (DILI) is one of the common adverse drug reactions in clinical practice, and it is difficult to diagnose and treat and may easily develop into acute liver failure. Related pharmacogenomics studies have found a strong genetic correlation between human leukocyte antigen (HLA) genes and DILI. This article reviews the research advances in HLA gene polymorphism in DILI, in order to reveal the role of immune factors in the pathogenesis of DILI, identify related genetic biomarkers, and improve the safety of clinical medication.
- Chemical and Drug Induced Liver Injury /
- HLA Antigens /
- Polymorphism, Single Nucleotide

HTML全文

表 1 HLA基因多态性与常见DILI的相关性

药物	HLA基因	人群	OR	参考文献
阿莫西林-克拉维酸	DRB1^*15:01	苏格兰	9.25	[12]
阿莫西林-克拉维酸	DRB1^15:01-DQB1^06:02	欧洲	3.3	[7]
阿莫西林-克拉维酸	A^*02:01	欧洲	2.2	[7]
氟氯西林	B^*57:01	英国	80.6	[8]
米诺环素	A^*35:02	高加索	29.6	[6]
甲氧苄啶-磺胺甲噁唑	B^*14:01	欧翳美国人	9.2	[32]
甲氧苄啶-磺胺甲噁唑	B^*35:01	非翳美国人	-	[32]
希美加群	DRB1^07-DQA1^02	英国	4.4	[18]
拉帕替尼	DRB1^*07:01	高加索	6.9~14.1	[34-35]
拉帕替尼	DRA1^*02:01	高加索	9.0~14.1	[34-35]
帕唑帕尼	B^*57:01	全球	-	[36]
何首乌	B^*35:01	中国	86.5¹⁾	[43]
何首乌	B^*35:01	中国	143.9²⁾	[43]
卡马西平	A^*31:01	欧洲	7.3	[39]
英夫利昔单抗	B^*39:01	欧洲	43.6	[44]
氟吡汀	DRB1^16:01-DQB1^05:02	德国	18.7	[38]
注：1)治疗对照组；2)人群对照组。

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参考文献(46)

[1]	Drug-induced Liver Disease Study Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol, 2015, 31(11): 1752-1769.(in Chinese) DOI: 10.3969/j.issn.1001-5256.2015.11.002 中华医学会肝病学分会药物性肝病学组. 药物性肝损伤诊治指南[J]. 临床肝胆病杂志, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002
[2]	KULLAK-UBLICK GA, ANDRADE RJ, MERZ M, et al. Drug-induced liver injury: Recent advances in diagnosis and risk assessment[J]. Gut, 2017, 66(6): 1154-1164. DOI: 10.1136/gutjnl-2016-313369
[3]	VEGA M, VERMA M, BESWICK D, et al. The incidence of drug- and herbal and dietary supplement-induced liver injury: Preliminary findings from gastroenterologist-based surveillance in the population of the state of delaware[J]. Drug Saf, 2017, 40(9): 783-787. DOI: 10.1007/s40264-017-0547-9
[4]	SHEN T, LIU YX, SHANG J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156(8): 2230-2241. DOI: 10.1053/j.gastro.2019.02.002
[5]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261. DOI: 10.1016/j.jhep.2019.02.014
[6]	URBAN TJ, NICOLETTI P, CHALASANI N, et al. Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B^*35:02 as a risk factor[J]. J Hepatol, 2017, 67(1): 137-144. DOI: 10.1016/j.jhep.2017.03.010
[7]	LUCENA MI, MOLOKHIA M, SHEN Y, et al. Susceptibility to amoxicillin-clavulanate- induced liver injury is influenced by multiple HLA class I and Ⅱ alleles[J]. Gastroenterology, 2011, 141(1): 338-347. DOI: 10.1053/j.gastro.2011.04.001
[8]	DALY AK, DONALDSON PT, BHATNAGAR P, et al. HLA-B^*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin[J]. Nat Genet, 2009, 41(7): 816-819. DOI: 10.1038/ng.379
[9]	AITHAL GP, GROVE JI. Genome-wide association studies in drug-induced liver injury: Step change in understanding the pathogenesis[J]. Semin Liver Dis, 2015, 35(4): 421-431. DOI: 10.1055/s-0035-1567829
[10]	URBAN TJ, DALY AK, AITHAL GP. Genetic basis of drug-induced liver injury: Present and future[J]. Semin Liver Dis, 2014, 34(2): 123-133. DOI: 10.1055/s-0034-1375954
[11]	FAN WL, SHIAO MS, HUI RC, et al. HLA association with drug-induced adverse reactions[J]. J Immunol Res, 2017, 2017: 3186328. http://www.ncbi.nlm.nih.gov/pubmed/29333460
[12]	GROVE JI, AITHAL GP. Human leukocyte antigen genetic risk factors of drug-induced liver toxicology[J]. Expert Opin Drug Metab Toxicol, 2015, 11(3): 395-409. DOI: 10.1517/17425255.2015.992414
[13]	USUI T, NAISBITT DJ. Human leukocyte antigen and idiosyncratic adverse drug reactions[J]. Drug Metab Pharmacokinet, 2017, 32(1): 21-30. DOI: 10.1016/j.dmpk.2016.11.003
[14]	CHIPINDA I, HETTICK JM, SIEGEL PD. Haptenation: Chemical reactivity and protein binding[J]. J Allergy (Cairo), 2011, 2011: 839682. http://www.ncbi.nlm.nih.gov/pubmed/21785613
[15]	YANG X, TU RF, YANG JH. Research advances in drug-induced liver injury[J]. J Clin Hepatol, 2020, 36(3): 509-513. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2020.03.006 杨雪, 涂荣芳, 杨晋辉. 药物性肝损伤的研究进展[J]. 临床肝胆病杂志, 2020, 36(3): 509-513. DOI: 10.3969/j.issn.1001-5256.2020.03.006
[16]	BAI ZF, GAO Y, ZUO XB, et al. Progress in research on the pathogenesis of immune regulation and idiosyncratic drug-induced liver injury[J]. Acta Pharmaceutica Sinica, 2017, 52 (7): 1019-1026. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-YXXB201707001.htm 柏兆方, 高源, 左晓彬, 等. 免疫调控与特异质型药物性肝损伤发生机制研究进展[J]. 药学学报, 2017, 52(7): 1019-1026. https://www.cnki.com.cn/Article/CJFDTOTAL-YXXB201707001.htm
[17]	WUILLEMIN N, ADAM J, FONTANA S, et al. HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin[J]. J Immunol, 2013, 190(10): 4956-4964. DOI: 10.4049/jimmunol.1202949
[18]	KINDMARK A, JAWAID A, HARBRON CG, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis[J]. Pharmacogenomics J, 2008, 8(3): 186-195. DOI: 10.1038/sj.tpj.6500458
[19]	PIRMOHAMED M, OSTROV DA, PARK BK. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity[J]. J Allergy Clin Immunol, 2015, 136(2): 236-244. DOI: 10.1016/j.jaci.2015.06.022
[20]	ILLING PT, MIFSUD NA, PURCELL AW. Allotype specific interactions of drugs and HLA molecules in hypersensitivity reactions[J]. Curr Opin Immunol, 2016, 42: 31-40. DOI: 10.1016/j.coi.2016.05.003
[21]	WATKINS S, PICHLER WJ. Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition[J]. PLoS One, 2013, 8(10): e76211. DOI: 10.1371/journal.pone.0076211
[22]	CHALASANI NP, HAYASHI PH, BONKOVSKY HL, et al. ACG Clinical Guideline: The diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2014, 109(7): 950-966; quiz 967. DOI: 10.1038/ajg.2014.131
[23]	HAUTEKEETE ML, HORSMANS Y, VAN WAEYENBERGE C, et al. HLA association of amoxicillin-clavulanate--induced hepatitis[J]. Gastroenterology, 1999, 117(5): 1181-1186. DOI: 10.1016/S0016-5085(99)70404-X
[24]	DONALDSON PT, DALY AK, HENDERSON J, et al. Human leucocyte antigen class Ⅱ genotype in susceptibility and resistance to co-amoxiclav-induced liver injury[J]. J Hepatol, 2010, 53(6): 1049-1053. DOI: 10.1016/j.jhep.2010.05.033
[25]	STEPHENS C, LÓPEZ-NEVOT MÁ, RUIZ-CABELLO F, et al. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity[J]. PLoS One, 2013, 8(7): e68111. DOI: 10.1371/journal.pone.0068111
[26]	MA Q, YANG W, WANG L, et al. Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen[J]. Int Immunopharmacol, 2020, 81: 106037. DOI: 10.1016/j.intimp.2019.106037
[27]	WING K, BHASKARAN K, PEALING L, et al. Quantification of the risk of liver injury associated with flucloxacillin: A UK population-based cohort study[J]. J Antimicrob Chemother, 2017, 72(9): 2636-2646. DOI: 10.1093/jac/dkx183
[28]	WUILLEMIN N, TERRACCIANO L, BELTRAMINELLI H, et al. T cells infiltrate the liver and kill hepatocytes in HLA-B(*)57:01-associated floxacillin-induced liver injury[J]. Am J Pathol, 2014, 184(6): 1677-1682. DOI: 10.1016/j.ajpath.2014.02.018
[29]	MONSHI MM, FAULKNER L, GIBSON A, et al. Human leukocyte antigen (HLA)-B^*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury[J]. Hepatology, 2013, 57(2): 727-739. DOI: 10.1002/hep.26077
[30]	NICOLETTI P, AITHAL GP, CHAMBERLAIN TC, et al. Drug-induced liver injury due to flucloxacillin: Relevance of multiple human leukocyte antigen alleles[J]. Clin Pharmacol Ther, 2019, 106(1): 245-253. DOI: 10.1002/cpt.1375
[31]	BJÖRNSSON E, TALWALKAR J, TREEPRASERTSUK S, et al. Drug-induced autoimmune hepatitis: Clinical characteristics and prognosis[J]. Hepatology, 2010, 51(6): 2040-2048. DOI: 10.1002/hep.23588
[32]	LI YJ, PHILLIPS E, DELLINGER A, et al. HLA-B^14: 01 and HLA-B^35: 01 are associated with trimethoprim-sulfamethoxazole induced liver injury[J]. Hepatology, 2020.[Epub ahead of print]
[33]	CHALASANI N, BONKOVSKY HL, FONTANA R, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study[J]. Gastroenterology, 2015, 148(7): 1340-1352. DOI: 10.1053/j.gastro.2015.03.006
[34]	SCHAID DJ, SPRAGGS CF, MCDONNELL SK, et al. Prospective validation of HLA-DRB1^*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury[J]. J Clin Oncol, 2014, 32(22): 2296-2303. DOI: 10.1200/JCO.2013.52.9867
[35]	SPRAGGS CF, BUDDE LR, BRILEY LP, et al. HLA-DQA1^*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer[J]. J Clin Oncol, 2011, 29(6): 667-673. DOI: 10.1200/JCO.2010.31.3197
[36]	XU CF, JOHNSON T, WANG X, et al. HLA-B^*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer[J]. Clin Cancer Res, 2016, 22(6): 1371-1377. DOI: 10.1158/1078-0432.CCR-15-2044
[37]	XIANG Q, ZHANG Z, WU Y, et al. HLA polymorphisms and TKI-induced liver injury in patients with cancer: A Meta-analysis[J]. J Cancer, 2019, 10(10): 2161-2168. DOI: 10.7150/jca.26727
[38]	NICOLETTI P, WERK AN, SAWLE A, et al. HLA-DRB1^16:01-DQB1^05:02 is a novel genetic risk factor for flupirtine-induced liver injury[J]. Pharmacogenet Genomics, 2016, 26(5): 218-224. DOI: 10.1097/FPC.0000000000000209
[39]	NICOLETTI P, BARRETT S, MCEVOY L, et al. Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions[J]. Clin Pharmacol Ther, 2019, 106(5): 1028-1036. DOI: 10.1002/cpt.1493
[40]	WANG XL, HUANG JJ, WANG B, et al. Correlation between HLA-B and drug induced liver injury caused by atypical antipsychotics[J]. J Pschiatry, 2016, 29(5): 346-349. (in Chinese) DOI: 10.3969/j.issn.2095-9346.2016.05.008 王晓良, 黄晶晶, 王飚, 等. HLA基因多态性与非典型抗精神病药物性肝损伤关联性研究[J]. 精神医学杂志, 2016, 29(5): 346-349. DOI: 10.3969/j.issn.2095-9346.2016.05.008
[41]	WANG R, QI X, YOSHIDA EM, et al. Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: A systematic review[J]. Expert Rev Gastroenterol Hepatol, 2018, 12(4): 425-434. DOI: 10.1080/17474124.2018.1427581
[42]	LEI X, CHEN J, REN J, et al. Liver damage associated with polygonum multiflorum thunb.: A systematic review of case reports and case series[J]. Evid Based Complement Alternat Med, 2015, 2015: 459749. http://www.ncbi.nlm.nih.gov/pubmed/25648693
[43]	LI C, RAO T, CHEN X, et al. HLA-B^*35:01 allele is a potential biomarker for predicting polygonum multiflorum-induced liver injury in humans[J]. Hepatology, 2019, 70(1): 346-357. http://www.ncbi.nlm.nih.gov/pubmed/30985007
[44]	BRUNO CD, FREMD B, CHURCH RJ, et al. HLA associations with infliximab-induced liver injury[J]. Pharmacogenomics J, 2020, 20(5): 681-686. DOI: 10.1038/s41397-020-0159-0
[45]	BJÖRNSSON ES, GUNNARSSON BI, GRÖNDAL G, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists[J]. Clin Gastroenterol Hepatol, 2015, 13(3): 602-608. DOI: 10.1016/j.cgh.2014.07.062
[46]	BJÖRNSSON ES, BERGMANN OM, BJÖRNSSON HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland[J]. Gastroenterology, 2013, 144(7): 1419-1425. DOI: 10.1053/j.gastro.2013.02.006