<i>KIR2DL4</i>及其配体<i>HLA-G</i>基因多态性与HCV易感性和慢性化关系

冯泽沛; 陈琼; 张津玮; 黄鹏; 尹荣; 曾添; 贾林娜; 喻荣彬; 张云; 岳明

doi:10.11847/zgggws1138229

KIR2DL4及其配体HLA-G基因多态性与HCV易感性和慢性化关系

doi: 10.11847/zgggws1138229

冯泽沛¹,
陈琼²,
张津玮³,
黄鹏^{1, 4},
尹荣⁵,
曾添⁶,
贾林娜¹,
喻荣彬¹,
张云^{1, 2, 4, ,},
岳明^6, ,

1.
南京医科大学公共卫生学院流行病与卫生统计学系传染病重点实验室，江苏南京 211166
2.
东部战区疾病预防控制中心传染病防控科
3.
南京大学医学院附属鼓楼医院麻醉科
4.
南京医科大学全球健康中心
5.
江苏省肿瘤医院胸外科
6.
南京医科大学第一附属医院感染病科

基金项目: 国家自然科学基金（81773499）；江苏省优秀青年基金（BK20190106）；云南省自然科学基金重点项目（2019FA005）；新发突发呼吸系统传染病临床研究中心（HS2020002）

详细信息

作者简介:
冯泽沛（1997 – ），男，湖北十堰人，硕士在读，研究方向：传染病流行病学

通讯作者:
张云，E-mail：zhangyunvip@126.com

岳明，E-mail：yueming@njmu.edu.cn

中图分类号: R 183
计量
- 文章访问数: 29
- HTML全文浏览量: 8
- PDF下载量: 6
- 被引次数: 0
出版历程
- 收稿日期: 2022-02-15
- 网络出版日期: 2023-01-10

Association of genetic variants of KIR2DL4 and its ligand HLA-G gene with HCV susceptibility and chronicity

1.
Key Laboratory of Infectious Disease, Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province 211166, China

摘要

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。
- 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.
- hepatitis C virus /
- susceptibility /
- chronicity /
- single nucleotide polymorphism

HTML全文

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
多态性位点	基因型	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。

下载: 导出CSV

参考文献(22)

[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