原发性胆汁性胆管炎遗传易感性的研究现状

赵春梅; 马狄; 邰文琳

doi:10.12449/JCH240328

原发性胆汁性胆管炎遗传易感性的研究现状

DOI: 10.12449/JCH240328

昆明医科大学第二附属医院检验科，昆明 650032

基金项目:

国家自然科学基金 (82060385);

昆明医科大学2023年研究生创新基金 (2023S321)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：赵春梅负责文献查找、阅读及文章撰写；马狄负责撰写框架的构建；邰文琳负责文章修改。

详细信息

通信作者:
邰文琳， taiwenlinlin@sohu.com （ORCID： 0000-0002-8278-929X）

计量
- 文章访问数: 291
- HTML全文浏览量: 143
- PDF下载量: 47
- 被引次数: 0
出版历程
- 收稿日期: 2023-06-27
- 录用日期: 2023-07-20
- 出版日期: 2024-03-20

Current status of research on the genetic susceptibility of primary biliary cholangitis

Department of Clinical Laboratory，The Second Affiliated Hospital of Kunming Medical University，Kunming 650032，China

Research funding:

National Natural Science Foundation of China (82060385);

Postgraduate Innovation Fund of Kunming Medical University in 2023 (2023S321)

More Information

Corresponding author: TAI Wenlin， taiwenlinlin@sohu.com （ORCID： 0000-0002-8278-929X）

摘要

摘要: 原发性胆汁性胆管炎（PBC）是一种以胆管上皮细胞变性坏死为主，好发于中老年女性，具有强烈的遗传倾向性的肝脏自身免疫性疾病。随着全基因组关联分析（GWAS）的不断发展，PBC的遗传易感性备受关注。本文阐述了与PBC密切相关的遗传易感基因的研究进展，以期为PBC治疗提供有效靶点。
- 原发性胆汁性胆管炎 /
- 疾病遗传易感性 /
- HLA抗原
Abstract: Primary biliary cholangitis （PBC） is a liver autoimmune disease with a strong genetic tendency characterized by the degeneration and necrosis of bile duct epithelial cells， and it is often observed in middle-aged and elderly women. With the continuous development of genome-wide association studies， the genetic susceptibility of PBC has attracted more and more attention. This article elaborates on the research advances in the genetic susceptibility genes closely associated with PBC， in order to provide effective targets for the treatment of PBC.
- Primary Biliary Cholangitis /
- Genetic Predisposition to Disease /
- HLA Antigens

HTML全文

表 1 与中国PBC显著相关的易感位点

Table 1. Susceptible loci significantly associated with Chinese PBC

候选基因	基因位置	SNP	组合P值	比值比（95%可信区间）
HLA-DRA	6p21	rs9268644	2.41×10^-19	0.51（0.44～0.59）
HLA-DPB1	6p21	rs9501251	8.17×10^-13	1.94（1.61～2.33）
IL1RL1	2q12.1	rs12712133	5.19×10^-9	1.14（1.07～1.21）
IL-12A	3q25.33	rs485499	4.20×10^-2	1.20（1.01～1.44）
IL-12RB2	1p31.3	rs11209050	4.00×10^-4	1.27（1.11～1.44）
CXCR5	11q23.3	rs715412	1.30×10^-2	1.26（1.05～1.52）
DDX6，CXCR5	11q23.3	rs77871618	9.12×10^-14	1.55（1.38～1.74）
CCL20	2q36.3	rs4973341	2.34×10^-10	0.82（0.74～0.90）
TNFSF15，TNFSF8	9q32	rs4979467	8.28×10^-12	1.40（1.27～1.54）
TNFRSF1A	12p13.31	rs4149576	1.11×10^-5	1.35（1.18～1.55）
TNFAIP3	6q23.3	rs6933404	1.27×10^-10	1.18（1.09～1.27）
ORMDL3，GSDMB，IKZF3	17q12		5.58×10^-7	1.38^1）
SNRPGP8	2q36.3	rs4973341	2.34×10^-10	0.82（0.74～0.90）
ARID3A	19p13.3	rs2238571	5.24×10^-10	0.77^1）
FCRL3	1q32.1	rs117214467	8.55×10^-3
DNMT3A	3q24.2	rs6807549	1.37×10^-3
RARB	4q24	rs79109654	8.56×10^-5
TRIM14	10q11.23	rs76129863	4.83×10^-3
WDFY4	11p15.5	rs3216	8.17×10^-2
TMEM163	6q21	rs4134466	6.71×10^-7
RPL3，SYNGR1	22q13.1	rs137603	2.06×10^-7	0.68（0.59～0.79）
HELZ2	20q13.33	rs79267778	1.87×10^-4	4.20（1.67～10.58）
注：1）95%可信区间无法获取；SNP，单核苷酸多态性。

下载: 导出CSV

参考文献(50)

[1]	YANG HQ, CHEN LL, LIU YH. A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis[J]. Front Immunol, 2023, 14: 1052616. DOI: 10.3389/fimmu.2023.1052616.
[2]	YOU H, MA X, EFE C, et al. APASL clinical practice guidance: The diagnosis and management of patients with primary biliary cholangitis[J]. Hepatol Int, 2022, 16( 1): 1- 23. DOI: 10.1007/s12072-021-10276-6.
[3]	AHOUSSOUGBEMEY MELE A, MAHMOOD R, OGBUAGU H, et al. Hyperlipidemia in the setting of primary biliary cholangitis: A case report and review of management strategies[J]. Cureus, 2022, 14( 11): e31411. DOI: 10.7759/cureus.31411.
[4]	COLAPIETRO F, LLEO A, GENERALI E. Antimitochondrial antibodies: From bench to bedside[J]. Clin Rev Allergy Immunol, 2022, 63( 2): 166- 177. DOI: 10.1007/s12016-021-08904-y.
[5]	QIAN Q, HE W, TANG R, et al. Implications of gut microbiota in autoimmune liver diseases[J]. Minerva Gastroenterol(Torino), 2023, 69( 1): 95- 106. DOI: 10.23736/S2724-5985.21.02860-9.
[6]	ÖRNOLFSSON KT, OLAFSSON S, BERGMANN OM, et al. Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis[J]. Hepatology, 2018, 68( 1): 166- 171. DOI: 10.1002/hep.29675.
[7]	SELMI C, MAYO MJ, BACH N, et al. Primary billiary cirrhosis in monozygotic twins: genetics, epigenetics, and environment[J]. Gastroenterology, 2004, 127( 2): 485- 492. DOI: 10.1053/j.gastro.2004.05.005.
[8]	ALWABEL AH, PEEDIKAYIL M, ALNASSER S, et al. Efficacy of ursodeoxycholic acid for primary biliary cholangitis: Experience from a tertiary care centre in Saudi Arabia[J]. Saudi J Gastroenterol, 2023, 29( 2): 135- 140. DOI: 10.4103/sjg.sjg_445_21.
[9]	GERUSSI A, CRISTOFERI L, CARBONE M, et al. The immunobiology of female predominance in primary biliary cholangitis[J]. J Autoimmun, 2018, 95: 124- 132. DOI: 10.1016/j.jaut.2018.10.015.
[10]	GOLDEN LC, ITOH Y, ITOH N, et al. Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes[J]. PNAS, 2019, 116( 52): 26779- 26787. DOI: 10.1073/pnas.1910072116.
[11]	CAO H, ZHU BK, QU Y, et al. Abnormal expression of ERα in cholangiocytes of patients with primary biliary cholangitis mediated intrahepatic bile duct inflammation[J]. Front Immunol, 2019, 10: 2815. DOI: 10.3389/fimmu.2019.02815.
[12]	QIU F, TANG RQ, ZUO XB, et al. A genome-wide association study identifies six novel risk loci for primary biliary cholangitis[J]. Nat Commun, 2017, 8: 14828. DOI: 10.1038/ncomms14828.
[13]	LI Y, LI ZQ, CHEN RL, et al. A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression[J]. Nat Commun, 2023, 14: 1732. DOI: 10.1038/s41467-023-37213-5.
[14]	CORDELL HJ, FRYETT JJ, UENO K, et al. Corrigendum to:“An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs”[J Hepatol 75(2021) 572-581][J]. J Hepatol, 2023, 78( 4): 883. DOI: 10.1016/j.jhep.2022.12.001.
[15]	DONG M, LI JX, TANG RQ, et al. Multiple genetic variants associated with primary biliary cirrhosis in a Han Chinese population[J]. Clin Rev Allergy Immunol, 2015, 48( 2-3): 316- 321. DOI: 10.1007/s12016-015-8472-0.
[16]	HITOMI Y, NAKAMURA M. The genetics of primary biliary cholangitis: A GWAS and post-GWAS update[J]. Genes, 2023, 14( 2): 405. DOI: 10.3390/genes14020405.
[17]	HUANG YQ. Recent advances in the diagnosis and treatment of primary biliary cholangitis[J]. World J Hepatol, 2016, 8( 33): 1419. DOI: 10.4254/wjh.v8.i33.1419.
[18]	JOSHITA S, UMEMURA T, TANAKA E, et al. Genetics and epigenetics in the pathogenesis of primary biliary cholangitis[J]. Clin J Gastroenterol, 2018, 11( 1): 11- 18. DOI: 10.1007/s12328-017-0799-z.
[19]	CHUNG BK, GUEVEL BT, REYNOLDS GM, et al. Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis[J]. J Autoimmun, 2017, 77: 45- 54. DOI: 10.1016/j.jaut.2016.10.003.
[20]	DARLAY R, AYERS KL, MELLS GF, et al. Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis[J]. PLoS Genet, 2018, 14( 12): e1007833. DOI: 10.1371/journal.pgen.1007833.
[21]	LIU X, INVERNIZZI P, LU Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis[J]. Nat Genet, 2010, 42( 8): 658- 660. DOI: 10.1038/ng.627.
[22]	WANG C, ZHENG XD, TANG RQ, et al. Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis[J]. J Autoimmun, 2020, 107: 102372. DOI: 10.1016/j.jaut.2019.102372.
[23]	GERUSSI A, CARBONE M, CORPECHOT C, et al. The genetic architecture of primary biliary cholangitis[J]. Eur J Med Genet, 2021, 64( 9): 104292. DOI: 10.1016/j.ejmg.2021.104292.
[24]	LI YN, LIU X, WANG Y, et al. Novel HLA-DRB1 alleles contribute risk for disease susceptibility in primary biliary cholangitis[J]. Dig Liver Dis, 2022, 54( 2): 228- 236. DOI: 10.1016/j.dld.2021.04.010.
[25]	TANAKA A, LEUNG PSC, GERSHWIN ME. The genetics of primary biliary cholangitis[J]. Curr Opin Gastroenterol, 2019, 35( 2): 93- 98. DOI: 10.1097/MOG.0000000000000507.
[26]	CHOW IT, JAMES EA, GATES TJ, et al. Differential binding of pyruvate dehydrogenase complex-E2 epitopes by DRB108∶‍01 and DRB111∶01 is predicted by their structural motifs and correlates with disease risk[J]. J Immunol, 2013, 190( 9): 4516- 4524. DOI: 10.4049/jimmunol.1202445.
[27]	HUANG CY, ZHANG HP, HAN WJ, et al. Disease predisposition of human leukocyte antigen class II genes influences the gut microbiota composition in patients with primary biliary cholangitis[J]. Front Immunol, 2022, 13: 984697. DOI: 10.3389/fimmu.2022.984697.
[28]	GUO F, HAO YA, ZHANG L, et al. Asthma susceptibility gene ORMDL3 promotes autophagy in human bronchial epithelium[J]. Am J Respir Cell Mol Biol, 2022, 66( 6): 661- 670. DOI: 10.1165/rcmb.2021-0305oc.
[29]	JAMES BN, WEIGEL C, GREEN CD, et al. Neutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice[J]. FASEB J, 2023, 37( 3): e22799. DOI: 10.1096/fj.202201821R.
[30]	CHEN R, MICHAELOUDES C, LIANG YM, et al. ORMDL3 regulates cigarette smoke-induced endoplasmic reticulum stress in airway smooth muscle cells[J]. J Allergy Clin Immunol, 2022, 149( 4): 1445- 1457. e 5. DOI: 10.1016/j.jaci.2021.09.028.
[31]	XIANG BY, DENG CY, QIU F, et al. Single cell sequencing analysis identifies genetics-modulated ORMDL3⁺ cholangiocytes having higher metabolic effects on primary biliary cholangitis[J]. J Nanobiotechnol, 2021, 19( 1): 1- 21. DOI: 10.1186/s12951-021-01154-2.
[32]	SCHMIEDEL BJ, SEUMOIS G, SAMANIEGO-CASTRUITA D, et al. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells[J]. Nat Commun, 2016, 7: 13426. DOI: 10.1038/ncomms13426.
[33]	ZHANG YT, ZENG WH, XIA YM. TWEAK/Fn14 axis is an important player in fibrosis[J]. J Cell Physiol, 2021, 236( 5): 3304- 3316. DOI: 10.1002/jcp.30089.
[34]	POVEDA J, VÁZQUEZ-SÁNCHEZ S, SANZ AB, et al. TWEAK-Fn14as a common pathway in the heart and the kidneys in cardiorenal syndrome[J]. J Pathol, 2021: path. 5631. DOI: 10.1002/path.5631.
[35]	PASCOE AL, JOHNSTON AJ, MURPHY RM. Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration[J]. Cell Mol Life Sci, 2020, 77( 17): 3369- 3381. DOI: 10.1007/s00018-020-03495-x.
[36]	LIAO M, LIAO JW, QU JQ, et al. Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis[J]. Cell Death Discov, 2023, 9: 26. DOI: 10.1038/s41420-023-01326-z.
[37]	WANG GY, GARCIA V, LEE J, et al. Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model[J]. PLoS One, 2022, 17( 6): e0269383. DOI: 10.1371/journal.pone.0269383.
[38]	WANG N, CHEN P, SONG Y, et al. CD226 deficiency attenuates the homeostasis and suppressive capacity of Tr1 cells[J]. Mol Immunol, 2021, 132: 192- 198. DOI: 10.1016/j.molimm.2021.01.002.
[39]	BAI LF, JIANG JY, LI H, et al. Role of CD226 Rs763361 polymorphism in susceptibility to multiple autoimmune diseases[J]. Immunol Investig, 2020, 49( 8): 926- 942. DOI: 10.1080/08820139.2019.1703737.
[40]	CORDELL HJ, FRYETT JJ, UENO K, et al. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs[J]. J Hepatol, 2021, 75( 3): 572- 581. DOI: 10.1016/j.jhep.2021.04.055.
[41]	TANAKA A, LEUNG PSC, YOUNG HA, et al. Therapeutic and immunological interventions in primary biliary cholangitis: From mouse models to humans[J]. Arch Med Sci, 2018, 14( 4): 930- 940. DOI: 10.5114/aoms.2017.70995.
[42]	SUN QN, WANG QA, FENG N, et al. The expression and clinical significance of serum IL-17 in patients with primary biliary cirrhosis[J]. Ann Transl Med, 2019, 7( 16): 389. DOI: 10.21037/atm.2019.07.100.
[43]	DENG CW, LI WL, FEI YY, et al. Imbalance of the CD226/TIGIT immune checkpoint is involved in the pathogenesis of primary biliary cholangitis[J]. Front Immunol, 2020, 11: 1619. DOI: 10.3389/fimmu.2020.01619.
[44]	DOUGALL WC, KURTULUS S, SMYTH MJ, et al. TIGIT and CD96: New checkpoint receptor targets for cancer immunotherapy[J]. Immunol Rev, 2017, 276( 1): 112- 120. DOI: 10.1111/imr.12518.
[45]	ADAM L, ZOLDAN K, HOFMANN M, et al. Follicular T helper cell signatures in primary biliary cholangitis and primary sclerosing cholangitis[J]. Hepatol Commun, 2018, 2( 9): 1051- 1063. DOI: 10.1002/hep4.1226.
[46]	LI YY, WANG WB, TANG LB, et al. Chemokine(C-X-C motif) ligand 13 promotes intrahepatic chemokine(C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis[J]. Hepatology, 2015, 61( 6): 1998- 2007. DOI: 10.1002/hep.27725.
[47]	ZHOU ZQ, TONG DN, GUAN J, et al. Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis[J]. Int Immunopharmacol, 2017, 51: 76- 81. DOI: 10.1016/j.intimp.2017.08.004.
[48]	CIRULLI ET, GOLDSTEIN DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing[J]. Nat Rev Genet, 2010, 11( 6): 415- 425. DOI: 10.1038/nrg2779.
[49]	KUKSA PP, GREENFEST-ALLEN E, CIFELLO J, et al. Scalable approaches for functional analyses of whole-genome sequencing non-coding variants[J]. Hum Mol Genet, 2022, 31( R1): R62- R72. DOI: 10.1093/hmg/ddac191.
[50]	HIRSCHFIELD GM, CHAPMAN RW, KARLSEN TH, et al. The genetics of complex cholestatic disorders[J]. Gastroenterology, 2013, 144( 7): 1357- 1374. DOI: 10.1053/j.gastro.2013.03.053.