自身免疫性肝炎遗传机制研究进展

王新贤; 陈兰羽; 吕文良

doi:10.12449/JCH250830

自身免疫性肝炎遗传机制研究进展

DOI: 10.12449/JCH250830

中国中医科学院广安门医院感染疾病科，北京 100053

基金项目:

中国中医科学院科技创新工程重点项目 (CI2021A00801)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王新贤负责查阅和分析资料，拟定写作思路，撰写论文；陈兰羽负责选题，修改论文；吕文良指导撰写文章并最后定稿。

详细信息

通信作者:
吕文良， lvwenliang@sohu.com （ORCID： 0000-0002-4552-919X）

计量
- 文章访问数: 269
- HTML全文浏览量: 131
- PDF下载量: 37
- 被引次数: 0
出版历程
- 收稿日期: 2024-12-10
- 录用日期: 2025-02-11
- 出版日期: 2025-08-25

Research advances in the genetic mechanism of autoimmune hepatitis

Department of Infectious Diseases，Guang’anmen Hospital，China Academy of Chinese Medical Sciences，Beijing 100053，China

Research funding:

Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A00801)

More Information

Corresponding author: LYU Wenliang， lvwenliang@sohu.com （ORCID： 0000-0002-4552-919X）

摘要

摘要: 自身免疫性肝炎（AIH）是由免疫异常导致的慢性炎症性肝脏疾病，遗传是AIH发病的重要因素，通过对基因的分析研究发现，新的遗传标记能更加深入地了解AIH的发病风险、制订治疗措施。本文从人类白细胞抗原、单核苷酸多态性、表观遗传三个方面进行简要综述，为AIH的临床与科研提供参考。
- 肝炎，自身免疫性 /
- HLA抗原 /
- 单核苷酸多态性 /
- 表观基因组学
Abstract: Autoimmune hepatitis （AIH） is a chronic inflammatory liver disease caused by immune abnormalities. Genetic factors play an important role in AIH. The analysis of genes has shown that new genetic markers can help to deepen the understanding of the risk of AIH and develop treatment measures. This article reviews the research advances in human leukocyte antigen， single nucleotide polymorphism， and epigenetics， in order to provide a reference for clinical treatment and research on AIH.
- Hepatitis， Autoimmune /
- HLA Antigens /
- Single Nucleotide Polymorphism /
- Epigenomics

HTML全文

参考文献(50)

[1]	TERZIROLI BERETTA-PICCOLI B, MIELI-VERGANI G, VERGANI D. Autoimmmune hepatitis[J]. Cell Mol Immunol, 2022, 19( 2): 158- 176. DOI: 10.1038/s41423-021-00768-8.
[2]	GATSELIS NK, ZACHOU K, KOUKOULIS GK, et al. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics[J]. World J Gastroenterol, 2015, 21( 1): 60- 83. DOI: 10.3748/wjg.v21.i1.60.
[3]	Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the diagnosis and management of autoimmune hepatitis(2021)[J]. J Clin Hepatol, 2022, 38( 1): 42- 49. 中华医学会肝病学分会. 自身免疫性肝炎诊断和治疗指南(2021)[J]. 临床肝胆病杂志, 2022, 38( 1): 42- 49.
[4]	LAMBA M, NGU JH, STEDMAN CAM. Trends in incidence of autoimmune liver diseases and increasing incidence of autoimmune hepatitis[J]. Clin Gastroenterol Hepatol, 2021, 19( 3): 573- 579. e 1. DOI: 10.1016/j.cgh.2020.05.061.
[5]	TANAKA A, MORI M, MATSUMOTO K, et al. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan[J]. Hepatol Res, 2019, 49( 8): 881- 889. DOI: 10.1111/hepr.13342.
[6]	LI Y, YAN L, WANG R, et al. Serum immunoglobulin G levels predict biochemical and histological remission of autoimmune hepatitis type 1: A single-center experience and literature review[J]. Clin Rev Allergy Immunol, 2022, 62( 2): 292- 300. DOI: 10.1007/s12016-021-08833-w.
[7]	GREGORIO GV, PORTMANN B, REID F, et al. Autoimmune hepatitis in childhood: A 20-year experience[J]. Hepatology, 1997, 25( 3): 541- 547. DOI: 10.1002/hep.510250308.
[8]	WONG GW, YEONG T, LAWRENCE D, et al. Concurrent extrahepatic autoimmunity in autoimmune hepatitis: Implications for diagnosis, clinical course and long-term outcomes[J]. Liver Int, 2017, 37( 3): 449- 457. DOI: 10.1111/liv.13236.
[9]	HIGUCHI T, OKA S, FURUKAWA H, et al. Genetic risk factors for autoimmune hepatitis: Implications for phenotypic heterogeneity and biomarkers for drug response[J]. Hum Genomics, 2021, 15( 1): 6. DOI: 10.1186/s40246-020-00301-4.
[10]	ZACHOU K, MURATORI P, KOUKOULIS GK, et al. Review article: Autoimmune hepatitis: Current management and challenges[J]. Aliment Pharmacol Ther, 2013, 38( 8): 887- 913. DOI: 10.1111/apt.12470.
[11]	FLOREANI A, RESTREPO-JIMÉNEZ P, SECCHI MF, et al. Etiopathogenesis of autoimmune hepatitis[J]. J Autoimmun, 2018, 95: 133- 143. DOI: 10.1016/j.jaut.2018.10.020.
[12]	BÉLAND K, LAPIERRE P, ALVAREZ F. Influence of genes, sex, age and environment on the onset of autoimmune hepatitis[J]. World J Gastroenterol, 2009, 15( 9): 1025- 1034. DOI: 10.3748/wjg.15.1025.
[13]	CZAJA AJ. Epigenetic changes and their implications in autoimmune hepatitis[J]. Eur J Clin Invest, 2018, 48( 4): e12899. DOI: 10.1111/eci.12899.
[14]	MACKAY IR, TAIT BD. HLA associations with autoimmune-type chronic active hepatitis: Identification of B8-DRw3 haplotype by family studies[J]. Gastroenterology, 1980, 79( 1): 95- 98.
[15]	van GERVEN NMF, VERWER BJ, WITTE BI, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands[J]. Scand J Gastroenterol, 2014, 49( 10): 1245- 1254. DOI: 10.3109/00365521.2014.946083.
[16]	WEBB GJ, HIRSCHFIELD GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity[J]. J Autoimmun, 2016, 66: 25- 39. DOI: 10.1016/j.jaut.2015.08.016.
[17]	de BOER YS, van GERVEN NMF, ZWIERS A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1[J]. Gastroenterology, 2014, 147( 2): 443- 452. e 5. DOI: 10.1053/j.gastro.2014.04.022.
[18]	DONALDSON PT. Genetics in autoimmune hepatitis[J]. Semin Liver Dis, 2002, 22( 4): 353- 364. DOI: 10.1055/s-2002-35705.
[19]	van GERVEN NF, de BOER YS, ZWIERS A, et al. HLA-DRB103: 01 and HLA-DRB104:01 modify the presentation and outcome in autoimmune hepatitis type-1[J]. Genes Immun, 2015, 16( 4): 247- 252. DOI: 10.1038/gene.2014.82.
[20]	FURUMOTO Y, ASANO T, SUGITA T, et al. Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis[J]. BMC Gastroenterol, 2015, 15: 144. DOI: 10.1186/s12876-015-0360-9.
[21]	CZAJA AJ, CARPENTER HA, MOORE SB. Clinical and HLA phenotypes of type 1 autoimmune hepatitis in North American patients outside DR3 and DR4[J]. Liver Int, 2006, 26( 5): 552- 558. DOI: 10.1111/j.1478-3231.2006.01249.x.
[22]	PANDO M, LARRIBA J, FERNANDEZ GC, et al. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition[J]. Hepatology, 1999, 30( 6): 1374- 1380. DOI: 10.1002/hep.510300611.
[23]	VÁZQUEZ-GARCÍA MN, ALÁEZ C, OLIVO A, et al. MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis[J]. J Hepatol, 1998, 28( 6): 985- 990. DOI: 10.1016/s0168-8278(98)80347-4.
[24]	KIRSTEIN MM, METZLER F, GEIGER E, et al. Prediction of short-and long-term outcome in patients with autoimmune hepatitis[J]. Hepatology, 2015, 62( 5): 1524- 1535. DOI: 10.1002/hep.27983.
[25]	DUARTE-REY C, PARDO AL, RODRÍGUEZ-VELOSA Y, et al. HLA class II association with autoimmune hepatitis in Latin America: A meta-analysis[J]. Autoimmun Rev, 2009, 8( 4): 325- 331. DOI: 10.1016/j.autrev.2008.11.005.
[26]	SHANKARKUMAR U, AMARAPURKAR DN, KANKONKAR S. Human leukocyte antigen allele associations in type-1 autoimmune hepatitis patients from western India[J]. J Gastroenterol Hepatol, 2005, 20( 2): 193- 197. DOI: 10.1111/j.1440-1746.2004.03608.x.
[27]	MARIA A, SOOD V, KHANNA R, et al. Association of HLA DRB1 allele profile with pediatric autoimmune liver disease in India[J]. J Clin Exp Hepatol, 2023, 13( 3): 397- 403. DOI: 10.1016/j.jceh.2023.01.001.
[28]	DONALDSON PT. Genetics of liver disease: Immunogenetics and disease pathogenesis[J]. Gut, 2004, 53( 4): 599- 608. DOI: 10.1136/gut.2003.031732.
[29]	CZAJA AJ, DONALDSON PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis[J]. Immunol Rev, 2000, 174: 250- 259. DOI: 10.1034/j.1600-0528.2002.017401.x.
[30]	UMEMURA T, KATSUYAMA Y, YOSHIZAWA K, et al. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan[J]. PLoS One, 2014, 9( 6): e 100565. DOI: 10.1371/journal.pone.0100565.
[31]	DOHERTY DG, DONALDSON PT, UNDERHILL JA, et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis[J]. Hepatology, 1994, 19( 3): 609- 615. DOI: 10.1002/hep.1840190311.
[32]	CZAJA AJ, CARPENTER HA, SANTRACH PJ, et al. Significance of HLA DR4 in type 1 autoimmune hepatitis[J]. Gastroenterology, 1993, 105( 5): 1502- 1507. DOI: 10.1016/0016-5085(93)90157-8.
[33]	CZAJA AJ, STRETTELL MD, THOMSON LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis[J]. Hepatology, 1997, 25( 2): 317- 323. DOI: 10.1002/hep.510250211.
[34]	LI Y, ZHOU L, HUANG ZX, et al. Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1[J]. JHEP Rep, 2023, 6( 1): 100926. DOI: 10.1016/j.jhepr.2023.100926.
[35]	UMEMURA T, JOSHITA S, SAITO H, et al. KIR/HLA genotypes confer susceptibility and progression in patients with autoimmune hepatitis[J]. JHEP Rep, 2019, 1( 5): 353- 360. DOI: 10.1016/j.jhepr.2019.09.003.
[36]	CZAJA AJ, COOKSON S, CONSTANTINI PK, et al. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis[J]. Gastroenterology, 1999, 117( 3): 645- 652. DOI: 10.1016/s0016-5085(99)70458-0.
[37]	COOKSON S, CONSTANTINI PK, CLARE M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis[J]. Hepatology, 1999, 30( 4): 851- 856. DOI: 10.1002/hep.510300412.
[38]	YAMAZAKI T, UMEMURA T, JOSHITA S, et al. A cis-eQTL of HLA-DPB1 affects susceptibility to type 1 autoimmune hepatitis[J]. Sci Rep, 2018, 8( 1): 11924. DOI: 10.1038/s41598-018-30406-9.
[39]	MIGITA K, NAKAMURA M, ABIRU S, et al. Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population[J]. PLoS One, 2013, 8( 8): e71382. DOI: 10.1371/journal.pone.0071382.
[40]	ZANDANELL S, BALCAR L, SEMMLER G, et al. Genetic variants determine treatment response in autoimmune hepatitis[J]. J Pers Med, 2023, 13( 3): 540. DOI: 10.3390/jpm13030540.
[41]	AZARIADIS K, GATSELIS NK, LYBEROPOULOU A, et al. PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality[J]. J Transl Autoimmun, 2024, 9: 100243. DOI: 10.1016/j.jtauto.2024.100243.
[42]	FAN XL, YIN DD, MEN RT, et al. NUDT15 polymorphism confer increased susceptibility to thiopurine-induced leukopenia in patients with autoimmune hepatitis and related cirrhosis[J]. Front Pharmacol, 2019, 10: 346. DOI: 10.3389/fphar.2019.00346.
[43]	MIGITA K, KOMORI A, KOZURU H, et al. Circulating microRNA profiles in patients with type-1 autoimmune hepatitis[J]. PLoS One, 2015, 10( 11): e0136908. DOI: 10.1371/journal.pone.0136908.
[44]	HUANG C, XING X, XIANG XY, et al. microRNAs in autoimmune liver diseases: From diagnosis to potential therapeutic targets[J]. Biomed Pharmacother, 2020, 130: 110558. DOI: 10.1016/j.biopha.2020.110558.
[45]	HALÁSZ T, HORVÁTH G, PÁR G, et al. miR-122 negatively correlates with liver fibrosis as detected by histology and FibroScan[J]. World J Gastroenterol, 2015, 21( 25): 7814- 7823. DOI: 10.3748/wjg.v21.i25.7814.
[46]	BLAYA D, AGUILAR-BRAVO B, HAO FJ, et al. Expression of microRNA-155 in inflammatory cells modulates liver injury[J]. Hepatology, 2018, 68( 2): 691- 706. DOI: 10.1002/hep.29833.
[47]	CHEN L, LU FB, CHEN DZ, et al. BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis[J]. Mol Immunol, 2018, 93: 38- 46. DOI: 10.1016/j.molimm.2017.11.008.
[48]	SAEKI C, MATSUZAKI J, KURODA M, et al. Identification of circulating microRNAs as potential biomarkers for hepatic necroinflammation in patients with autoimmune hepatitis[J]. BMJ Open Gastroenterol, 2022, 9( 1): e000879. DOI: 10.1136/bmjgast-2022-000879.
[49]	PASHANGZADEH S, MOTALLEBNEZHAD M, VAFASHOAR F, et al. Implications the role of miR-155 in the pathogenesis of autoimmune diseases[J]. Front Immunol, 2021, 12: 669382. DOI: 10.3389/fimmu.2021.669382.
[50]	ZACHOU K, ARVANITI P, LYBEROPOULOU A, et al. Impact of genetic and environmental factors on autoimmune hepatitis[J]. J Transl Autoimmun, 2021, 4: 100125. DOI: 10.1016/j.jtauto.2021.100125.