原发性胆汁性胆管炎患者血浆细胞毒性T淋巴细胞相关蛋白4基因多态性分析

doi:10.3969/j.issn.1672-5069.2021.06.016

摘要/Abstract

摘要： 目的探讨原发性胆汁性胆管炎(PBC)患者血浆细胞毒性T淋巴细胞相关蛋白4(CTLA-4)基因多态性变化。方法 2015年9月～2020年12月我院诊治的PBC患者30例和同期健康体检者35例,采用聚合酶链反应-限制性片段长度多态性检测血浆CTLA－4基因rs231775、 rs4675369和rs7599230位点多态性。Logistic回归分析疾病风险关联。结果 PBC患者CTLA－4基因rs7599230位点基因型为CC型、CT型和TT型比率分别为16.7%、46.7%和36.6%,与健康人的20.0%、45.7%和34.3%比,无显著性差异(P＞0.05),等位基因C和T比率分别为40.0%和60.0%,与健康人群的42.9%和57.1%比,也无显著性差异(P＞0.05);PBC患者CTLA－4基因rs231775位点基因型为GG型和等位基因G比率分别为40.0%和61.7%,显著高于健康人的14.2%和35.7%(P＜0.05),AA基因型和等位基因A比率分别为16.7%和38.3%,显著低于健康人的42.9%和64.3%(P＜0.05);PBC患者CTLA－4基因rs4675369位点基因型为GG型和等位基因G比率分别为43.3%和65.0%,显著高于健康人的17.1%和41.4%(P＜0.05),AA基因型和等位基因A比率分别为13.4%和35.0%,显著低于健康人的34.3%和58.6%(P＜0.05);经非条件Logistic回归模型计算,校正性别和年龄,结果显示rs4675369位点GG基因型是影响PBC发生的危险基因型,其OR值为1.523((95%CI:1.113～2.085),rs231775位点GG基因型也是影响PBC发生的危险基因型,其OR值为1.636((95%CI:1.161～2.305) 。结论 CTLA-4基因rs231775和rs4675369位点GG基因型可能是PBC发生的易感基因型,值得进一步研究。

关键词: 原发性胆汁性胆管炎, 细胞毒性T淋巴细胞相关蛋白4, 基因多态性, 易感性

Abstract: Objective The aim of this study was to explore plasma cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene polymorphisms in patients with primary biliary cholangitis(PBC). Methods A total of 30 patients with PBC and 35 healthy persons were included in our hospital between September 2015 and December 2020, and the gene polymorphisms of CTLA-4 at rs231775, rs4675369 and rs7599230 loci were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Logistic regression analysis was applied to reveal the risk factors for PCB occurrence. Results The percentages of CTLA-4 genotypes (CC, CT, TT) at rs7599230 locus in patients with PBC were 16.7%, 46.7% and 36.6%, not significantly different compared with those in healthy persons (20.0%,45.7%, 34.3%, respectively, P>0.05), and the percentages of alleles (C, T) in patients with PBC were 40.0% and 60.0%, also not significantly different compared with those in healthy individuals (42.9% and 57.1%, respectively, P>0.05); the percentages of CTLA-4 genotype GG and allele G at rs231775 locus in patients with PBC were 40.0% and 61.7%, significantly higher than 14.2% and 35.7% in healthy persons (P<0.05), while the percentages of of AA genotype and allele A were 16.7% and 38.3%, significantly lower than 42.9% and 64.3% in healthy persons (P<0.05); the percentages of CTLA-4 genotype GG and allele G at rs4675369 locus in patients with PBC were 43.3% and 65.0%, significantly higher than 17.1% and 41.4% in healthy individuals (P<0.05), while the percentages of AA genotype and allele A were 13.4% and 35.0%, significantly lower than 34.3% and 58.6% in healthy control (P<0.05); after the correction of gender and age by unconditional Logistic regression model, we found that the GG genotype at rs4675369 locus (OR: 1.523, 95%CI: 1.113-2.085) and the GG genotype at rs231775 locus (OR:1.636, 95%CI: 1.161-2.305) were the risk genotype for the occurrence of PBC. Conclusion Our findings suggest that the GG genotype at rs231775 and rs4675369 loci of CTLA-4 gene might be the susceptible genotype for PBC occurrence, and needs further investigation.

Key words: Primary biliary cholangitis, Cytotoxic T lymphocyte associated antige-4, Gene polymorphism, Susceptibility

李衍强, 石慧, 王文珊, 林学贤, 王英运. 原发性胆汁性胆管炎患者血浆细胞毒性T淋巴细胞相关蛋白4基因多态性分析[J]. 实用肝脏病杂志, 2021, 24(6): 831-834.

Li Yanqiang, Shi Hui, Wang Wenshan, et al. Plasma cytotoxic T lymphocyte associated antigen-4 gene polymorphisms in patients with primary biliary cholangitis[J]. Journal of Practical Hepatology, 2021, 24(6): 831-834.

参考文献

[1] Johnson O O, Diggle P, Giorgi E . A spatially discrete approximation to log-Gaussian Cox processes for modelling aggregated disease count data. Stat Med, 2019, 38(24):4871-4887.
[2] Chen X, Ma X, Wang R, et al. Treatment of primary biliary cirrhosis with ursodeoxycholic acid combined with traditional Chinese medicine: A protocol for systematic review and meta analysis. Medicine, 2020, 99(46):e23107.
[3] Peng Y, Chen H, Huang L, et al. Mo1489 - risk factors for primary biliary cirrhosis combined withSjogren's syndrome: a cohort of Chinese patients from single center. Gastroenterology, 2019,156(6):1324-1325.
[4] Zhuo C, Yi T, Wei C, et al. Association of cytotoxic T lymphocyte-associated protein 4 gene -1772T/C polymorphism with gastric cancer risk: A prisma-compliant meta-analysis. Medicine, 2020,99(11):101-105.
[5] Min F, Chen H, Shu M. Associations between cytotoxic T-lymphocyte-associated antigen 4 gene polymorphisms and diabetes mellitus: a meta-analysis of 76 case-control studies. Biosci Rep, 2019,39(5):309-312.
[6] Wang L, Li Y, Wang N, et al. Association of cytotoxic T-lymphocyte associated protein 4 gene polymorphisms with the risk and prognosis of oesophageal cancer in a high-incidence region from northern China. Int J Immunogenet,2020,47(2):180-187.
[7] Ismail NA, Toraih EA, Ameen HM, et al. Association of Rs231775 genetic variant of cytotoxic T-lymphocyte associated protein 4 with alopecia areata disease in males: a case-control study. ImmunolInvest, 2020,15(1):1-10.
[8] 尹继红,王晓峰,王茹.CTLA-4基因多态性与儿童支气管哮喘易感性及血浆IFN-γ,IL-4,IgE的关系. 山东医药, 2020,60(4):10-13.
[9] 中华医学会肝病学分会、消化病学分会、感染病学分会.胆汁淤积性肝病诊断和治疗共识(2015年).实用肝脏病杂志,2016,19(6):I-XI.
[10] Eric CL, Tzakis AG, Andrews D. Response of factor V inhibitor to rituximab in a patient who received liver transplantation for primary biliary cirrhosis. Am J Hematol, 2018,77(9):363-365.
[11] Chen M, Li SM. Associations between cytotoxic T-lymphocyte-associated antigen 4 gene polymorphisms and diabetes mellitus: a meta-analysis of 76 case-control studies. Biosc Rep, 2019,39(5):309-313.
[12] Lammers WJ, Trivedi P, Hirschfield G, et al. Stratification of hepatocellular carcinoma risk using the GLOBE score in patients with primary biliary cholangitis- the Global PBC Study Group. J Hepatol,2018, 68(7):229-230.
[13] Lin B, Wang L. Correlative analysis between cytotoxic T lymphocyte antigen 4 genetic polymorphisms and head and neck cancer susceptibility: A protocol for systematic review and meta-analysis. Medicine, 2020,99(50):e23519.
[14] Abdulqader AM, Mohammed AI, Rachid S. Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A. J Int Med Res, 2019,47(10):32-38.
[15] 张冰,解学军.酒精性肝硬化患者血CTLA-4和PNPLA3基因多态性及其临床意义分析.实用肝脏病杂志,2020,23(1):86-89.
[16] Tang Z, Mo F, Liu A, et al. A nanobody against cytotoxic T-lymphocyte associated antigen-4 increases the anti-tumor effects of specific CD8⁺T cells. J Biomed Nanotechnol, 2019, 15(11):2229-2239.
[17] Masuda H, Nakamura T, Harashima H . Distribution of BCG-CWS-loaded nanoparticles in the spleen after intravenous injection affects cytotoxic T lymphocyte activity. J Pharm Sci, 2020,109(6):25-27.
[18] Min Y, Katrin K, Clara MH, et al. Regulatory T cells control epitope spreading in autoimmune arthritis independent of CTLA-4. Immunology, 2018,16(4):446-457.
[19] Liu X, Swen JJ, Diekstra MM, et al. A genetic polymorphism in CTLA-4Is associated with overall survival in sunitinib-treated patients with clear cell metastatic renal cell carcinoma. Clin Cancer Res, 2018, 24(10):2815-2817.
[20] Seamans BN, Pellechio SL, Capria AL, et al. Genetic diversity of CD14, CD28, CTLA-4 and ICOS gene promoter polymorphism in African and American sickle cell disease. Human Immunol 2019, 80(11):930-936.