Association of genetic variants of KIR2DL4 and its ligand HLA-G gene with HCV susceptibility and chronicity
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摘要:
目的 探讨KIR2DL4基因rs649216位点及其配体HLA-G基因rs1063320位点单核苷酸多态性(SNP)与丙型肝炎病毒(HCV)易感性和慢性化的关联性,为HCV感染预防筛查和诊断提供理论依据。 方法 于2011年10月 — 2015年12月采用整群抽样方法抽取江苏省南京市公安局强制隔离戒毒所和宜兴市强制戒毒所收治的1121例吸毒者及江苏省9家医院的733例肾透析者共1 854例18~80岁未接受过抗HCV治疗(包括干扰素和直接抗病毒药物)且随访 ≥ 6个月的HCV感染高危人群进行问卷调查和HCV抗体检测,将抗 – HCV和HCV RNA均为阴性的1341例作为阴性组、抗 – HCV阳性且HCV RNA阴性的301例作为自限清除组、抗 – HCV和HCV RNA均为阳性的212例作为持续感染组,采用TaqMan探针实时荧光定量聚合酶链式反应(PCR)进行基因分型,并应用多因素logistic回归模型分析KIR2DL4基因rs649216位点及其配体HLA-G基因rs1063320位点基因多态性与HCV易感性和慢性化的关系。 结果 阴性组KIR2DL4 rs649216位点CC、CT和TT型基因型携带者分别占69.15 %、28.15 %和2.69 %,自限清除组分别占73.90 %、23.05 %和3.05 %,持续感染组分别占62.25 %、33.82 %和3.92 %;阴性组HLA-G rs1063320位点GG、GC和CC型基因型携带者分别占32.89 %、51.25 %和15.86 %,自限清除组分别占34.29 %、45.36 %和20.36 %,持续感染组分别占33.15 %、47.28 %和19.57 %。在校正了性别、年龄、谷丙转氨酶(ALT)值是否异常、谷草转氨酶(AST)值是否异常和感染途径后,多因素非条件logistic回归分析结果显示,与携带KIR2DL4 rs649216位点CC基因型的个体相比,携带KIR2DL4 rs649216位点CT/TT基因型的个体HCV慢性化风险更高(共显性模型:OR = 1.682,95 % CI = 1.109~2.551,P = 0.014;显性模型:OR = 1.671,95 % CI = 1.121~2.493,P = 0.012);与携带KIR2DL4 rs649216位点C等位基因的个体相比,携带KIR2DL4 rs649216位点T等位基因的个体HCV慢性化风险更高(相加模型:OR = 1.508,95 % CI = 1.070~2.125,P = 0.019);与携带HLA-G rs1063320位点GG + GC基因型的个体相比,携带HLA-G rs1063320位点CC基因型的个体感染HCV风险更高(隐性模型:OR = 1.361,95 % CI = 1.018~1.819,P = 0.037)。 结论 KIR2DL4基因rs649216位点与HCV慢性化有关,其配体HLA-G rs1063320位点基因多态性与HCV易感性有关。 -
关键词:
- 丙型肝炎病毒(HCV) /
- 易感性 /
- 慢性化 /
- 单核苷酸多态性(SNP)
Abstract:Objective To explore effects of single nucleotide polymorphism (SNP) in KIR2DL4 rs649216 and its ligand HLA-G rs1063320 on hepatitis C virus (HCV) infection susceptibility and chronicity and to provide evidence for screening, diagnosis and prevention of HCV infection. Methods Totally 1 854 high-risk adults (18 – 80 years old) of HCV infection without the history of anti-HCV therapy (interferon or antiviral drugs treatment) were recruited with cluster sampling in two compulsory drug rehabilitation centers and hemodialysis rooms of 9 hospitals in two cities of Jiangsu province from October 2011 to December 2015; all the participants (1 121 drug addicts and 733 hemodialysis patients) were assigned into three groups according to the results of two separate HCV antibody and HCV RNA detections during previous 6 months before the survey: 1 341 in an uninfected group (negative for both HCV antibody and HCV RNA), 301 in a spontaneous HCV clearance group (positive for HCV antibody but negative for HCV RNA), and 202 in a persistent HCV infection group (positive for both HCV antibody and HCV RNA). Face-to-face questionnaire interview was conducted among the participants and fasting venous blood samples of the participants were collected for detections of HCV antibody, HCV RNA, HCV genotype, and genotype of targeted genes with TaqMan probe-based real-time quantitative PCR. Multivariate logistic regression model was adopted in analyses on the associations of SNP in KIR2DL4 rs649216 and its ligand HLA-G rs1063320 locus with HCV susceptibility and chronicity. Results The proportions for carriers of genotype CC, CT and TT of KIR2DL4 rs649216 were 69.15%, 28.15% and 2.69% in the uninfected group; 73.90%, 23.05% and 3.05% in the spontaneous clearance group; and 62.25%, 33.82% and 3.92% in the persistent infection group; while, those for carriers of genotype GG, GC and CC of HLA-G rs1063320 were 32.89%, 51.25% and15.86% in the uninfected group; 34.29%, 45.36% and 20.36% in the spontaneous clearance group; and 33.15%, 47.28% and 19.57% in the persistent infection group, respectively. After adjusting for gender, age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and infection route, unconditional multivariate logistic regression analyses showed that compared with the those with the genotype CC of KIR2DL4 rs649216, the participants with the genotype CT/TT of KIR2DL4 rs649216 were at a higher risk of chronic HCV infection (co-dominant model: odds ratio [OR] = 1.682, 95 % confidence interval [95% CI]: 1.109 – 2.551; dominant model: OR = 1.671, 95% CI: 1.121 – 2.493); the participants carrying allele T of KIR2DL4 rs649216 were at an increased risk of chronic HCV infection (additive model: OR = 1.508, 95% CI: 1.070 – 2.125) in comparison with those carrying allele C of KIR2DL4 rs649216; moreover, in comparison with those carrying genotype GG + GC of HLA-G rs1063320, the participants carrying genotype CC of HLA-G rs1063320 were more likely to have HCV infection (recessive model: OR = 1.361, 95% CI: 1.018 – 1.819). Conclusion The SNP of KIR2DL4 rs649216 is associated with the chronicity of HCV infection and the SNP of KIR2DL4’s ligand HLA-G rs1063320 is associated with the susceptibility to HCV infection. -
Key words:
- hepatitis C virus /
- susceptibility /
- chronicity /
- single nucleotide polymorphism
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表 1 KIR2DL4 rs649216位点和HLA-G rs1063320位点基因多态性与HCV易感性和慢性化关系多因素非条件logistic回归分析
多态性位点 基因型 阴性组 自限清除组 持续感染组 自限清除组 + 持续感染组vs.阴性组 持续感染组vs.自限清除组 n % n % n % P 值 OR 值 95 % CI P 值 OR 值 95 % CI rs649216 CC 899 69.15 218 73.90 127 62.25 1.000 1.000 CT 366 28.15 68 23.05 69 33.82 0.355 0.890 0.695~1.140 0.014 1.682 1.109~2.551 TT 35 2.69 9 3.05 8 3.92 0.439 1.283 0.683~2.411 0.382 1.587 0.564~4.465 显性模型 0.504 0.922 0.727~1.170 0.012 1.671 1.121~2.493 隐性模型 0.377 1.326 0.709~2.482 0.543 1.376 0.492~3.843 相加模型 0.759 0.968 0.787~1.191 0.019 1.508 1.070~2.125 rs1063320 GG 396 32.89 96 34.29 61 33.15 1.000 1.000 GC 617 51.25 127 45.36 87 47.28 0.694 0.949 0.733~1.229 0.894 1.031 0.659~1.613 CC 191 15.86 57 20.36 36 19.57 0.098 1.319 0.950~1.833 0.617 0.868 0.498~1.512 显性模型 0.764 1.038 0.814~1.323 0.917 0.978 0.643~1.486 隐性模型 0.037 1.361 1.018~1.819 0.522 0.853 0.523~1.390 相加模型 0.179 1.119 0.950~1.319 0.669 0.942 0.718~1.237 注:a 调整了性别、年龄、ALT值是否异常、AST值是否异常和感染途径等混杂因素。 -
[1] World Health Organization. Global hepatitis report, 2017[R]. Geneva: World Health Organization, 2017. [2] Spearman CW, Dusheiko GM, Hellard M, et al. Hepatitis C[J]. The Lancet, 2019, 394(10207): 1451 – 1466. doi: 10.1016/S0140-6736(19)32320-7 [3] 饶慧瑛, 李明阳, 魏来. 消除丙型肝炎, 我们的进展、挑战和希望[J]. 中华肝脏病杂志, 2020, 28(10): 809 – 811. doi: 10.3760/cma.j.cn501113-20200929-00538 [4] Li GD, De Clercq E. Current therapy for chronic hepatitis C: the role of direct-acting antivirals[J]. Antiviral Research, 2017, 142: 83 – 122. doi: 10.1016/j.antiviral.2017.02.014 [5] Larrat S, Vallet S, David-Tchouda S, et al. Naturally occurring resistance-associated variants of hepatitis C virus protease inhi-bitors in poor responders to pegylated interferon-ribavirin[J]. Journal of Clinical Microbiology, 2015, 53(7): 2195 – 2202. doi: 10.1128/JCM.03633-14 [6] Walker CM, Grakoui A. Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection?[J]. Current Opinion in Immunology, 2015, 35: 137 – 143. doi: 10.1016/j.coi.2015.06.010 [7] 符祖强, 葛志军, 黄鹏, 等. TNFRSF4和TNFSF4基因多态性与HCV感染关系[J]. 中国公共卫生, 2020, 36(12): 1813 – 1816. doi: 10.11847/zgggws1129981 [8] 李晓春, 阎瑞雪, 海燕, 等. 安钠咖滥用人群HCV感染影响因素分析[J]. 中国公共卫生, 2016, 32(11): 1524 – 1527. doi: 10.11847/zgggws2016-32-11-20 [9] Parham P, Guethlein LA. Genetics of natural killer cells in human health, disease, and survival[J]. Annual Review of Immunology, 2018, 36: 519 – 548. doi: 10.1146/annurev-immunol-042617-053149 [10] Zeng JM, Tang SY, Toh LL, et al. Generation of "off-the-shelf" natural killer cells from peripheral blood cell-derived induced pluripotent stem cells[J]. Stem Cell Reports, 2017, 9(6): 1796 – 1812. doi: 10.1016/j.stemcr.2017.10.020 [11] Catamo E, Zupin L, Freato N, et al. HLA-G regulatory polymor-phisms are associated with susceptibility to HCV infection[J]. HLA, 2017, 89(3): 135 – 142. doi: 10.1111/tan.12959 [12] Njiomegnie GF, Read SA, Fewings N, et al. Immunomodulation of the natural killer cell phenotype and response during HCV infection[J]. Journal of Clinical Medicine, 2020, 9(4): 1030. doi: 10.3390/jcm9041030 [13] Attia JVD, Dessens CE, Van De Water R, et al. The molecular and functional characteristics of HLA-G and the interaction with its receptors: where to intervene for cancer immunotherapy?[J]. International Journal of Molecular Sciences, 2020, 21(22): 8678. doi: 10.3390/ijms21228678 [14] Le Bouteiller P. HLA-G in human early pregnancy: control of uterine immune cell activation and likely vascular remodeling[J]. Biomedical Journal, 2015, 38(1): 32 – 38. doi: 10.4103/2319-4170.131376 [15] Kataoka TR, Ueshima C, Hirata M, et al. Killer immunoglobulin-like receptor 2DL4 (CD158d) regulates human mast cells both positively and negatively: possible roles in pregnancy and cancer metastasis[J]. International Journal of Molecular Sciences, 2020, 21(3): 954. doi: 10.3390/ijms21030954 [16] Shen C, Ge ZJ, Dong C, et al. Genetic variants in KIR/HLA-C genes are associated with the susceptibility to HCV infection in a high-risk Chinese population[J]. Frontiers in Immunology, 2021, 12: 632353. doi: 10.3389/fimmu.2021.632353 [17] Shan ZG, Huang JT, Liao Q, et al. Association of killer cell immunoglobulin-like receptors with spontaneous clearance of hepatitis C virus in the Chinese population[J]. Transfusion, 2018, 58(4): 1028 – 1035. doi: 10.1111/trf.14527 [18] Biswas A, Gupta N, Gupta D, et al. Association of TNF-alpha (-308 A/G) and IFN-gamma ( + 874 A/T) gene polymorphisms in response to spontaneous and treatment induced viral clearance in HCV infected multitransfused thalassemic patients[J]. Cytokine, 2018, 106: 148 – 153. doi: 10.1016/j.cyto.2017.10.026 [19] Tovo PA, Calitri C, Scolfaro C, et al. Vertically acquired hepatitis C virus infection: correlates of transmission and disease progression[J]. World Journal of Gastroenterology, 2016, 22(4): 1382 – 1392. doi: 10.3748/wjg.v22.i4.1382 [20] Ge YZ, Ge Q, Li MH, et al. Association between human leukocyte antigen-G 14-bp insertion/deletion polymorphism and cancer risk: a meta-analysis and systematic review[J]. Human Immunology, 2014, 75(8): 827 – 832. doi: 10.1016/j.humimm.2014.06.004 [21] Vicente LDM, Castelli EC, Veronese Rodrigues MDL, et al. Variability at the 3' untranslated region of the HLA-G gene: a study on patients with AIDS and cytomegalovirus retinochoroiditis[J]. Scientific Reports, 2020, 10: 18646. doi: 10.1038/s41598-020-75639-9 [22] Zhou SH, Liu M, Xia YX, et al. Association of the 3' untranslated region polymorphisms of HLA-G with susceptibility to chronic hepatitis C virus infection in the Chinese population[J]. Human Immunology, 2022, 83(1): 47 – 52. doi: 10.1016/j.humimm.2021.09.001 -

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