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FCGR3A和FCGR3B基因拷贝数变异对HBV感染转归的影响
DOI: 10.3969/j.issn.1001-5256.2022.06.012
伦理学声明：本研究于2012年2月18日通过安徽医科大学生物医学伦理委员会审核批准，批号：2012102。所有患者均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：李昊天、王同同负责实验和数据分析及文稿撰写；李绪桐负责数据收集及文献检索；郜玉峰负责文稿的构思、润色和最后定稿。
Influence of copy number variations in the FCGR3A and FCGR3B genes on the outcome of hepatitis B virus infection
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摘要:
目的 探讨FCGR3A和FCGR3B基因拷贝数变异与HBV感染后不同转归和疾病进展的相关性。 方法 收集2014年1月—2018年12月安徽医科大学第一附属医院和第二附属医院感染病科住院和门诊841例慢性HBV感染者和296例自限性HBV感染者外周血标本，并将慢性HBV感染者根据病情进展程度进一步分为慢性乙型肝炎(CHB)组、肝硬化(LC)组、肝细胞癌(HCC)组。采用AccuCopy技术定量分析两组患者外周血FCGR3A和FCGR3B基因拷贝数变异。计量资料两组间比较采用独立样本t检验，多组间比较采用单因素方差分析和Kruskal-Wallis H检验；计数资料组间比较采用χ2检验。同时采用χ2检验分析FCGR3基因CNV在不同组间的分布差异。应用年龄和性别校正的logistic回归模型综合分析CNV对HBV感染慢性化的影响。 结果 慢性HBV感染组与自限性HBV感染组的FCGR3A、FCGR3B拷贝数变异频率分布差异均有统计学意义(χ2值分别为11.406、19.143，P值均＜0.05)。在慢性HBV感染后疾病进展方面，CHB组、LC组、HCC组间比较FCGR3A、FCGR3B基因拷贝数变异差异无统计学意义(FCGR3A：χ2=3.125，P=0.537，FCGR3B：χ2=5.274，P=0.260)。而且FCGR3A、FCGR3B基因拷贝数变异在HBeAg阳性组和阴性组之间无统计学差异(FCGR3A：χ2=1.025，P=0.599，FCGR3B：χ2=0.712，P=0.701)。FCGR3A基因和FCGR3B基因拷贝数减少或缺失是HBV感染慢性化的危险因素[FCGR3A：OR=0.621，95%CI: 0.513~0.752，P＜0.001；FCGR3B：OR=0.594，95%CI: 0.491 ~0.719，P＜0.001]。 结论 FCGR3A基因和FCGR3B基因拷贝数减少或缺失可能是HBV感染慢性化的遗传易感因素之一，但与疾病进展无关。 Abstract:Objective To investigate the association of copy number variations (CNVs) in the FCGR3A and FCGR3B genes with different outcomes and disease progression after hepatitis B virus (HBV) infection. Methods Peripheral blood samples were collected from 841 patients with chronic HBV infection and 296 patients with self-limited HBV infection, an according to the degree of disease progression, the patients with chronic HBV infection were further divided into chronic hepatitis B (CHB) group, liver cirrhosis (LC) group, and hepatocellular carcinoma (HCC) group. The AccuCopy technique was used for the quantitative analysis of CNVs in the FCGR3A and FCGR3B genes in peripheral blood. The independent samples t-test was used for comparison of continuous data between two groups, and a one-way analysis of variance and the Kruskal-Wallis H test were used for comparison between multiple groups; the chi-square test was used for comparison of categorical data between groups. The chi-square test was also used to investigate the difference in the distribution of CNVs in the FCGR3 gene between different groups. The age-and sex-adjusted logistic regression model was used to investigate the influence of CNVs on the chronicity of HBV infection. Results There was a significant difference in the frequency distribution of CNVs in the FCGR3A and FCGR3B genes between the chronic HBV infection group and the self-limited HBV infection group (χ2=11.406 and 19.143, both P < 0.05). As for disease progression after chronic HBV infection, there were no significant differences in CNVs of the FCGR3A and FCGR3B genes between the CHB group, the LC group, and the HCC group (FCGR3A: χ2=3.125, P=0.537; FCGR3B: χ2=5.274, P=0.260). There were also no significant differences in CNVs of the FCGR3A and FCGR3B genes between the HBeAg-positive group and the HBeAg-negative group (FCGR3A: χ2=1.025, P=0.599; FCGR3B: χ2=0.712, P=0.701). Reduction or deletion of the copy number of the FCGR3A and FCGR3B genes was a risk factor for the chronicity of HBV infection (FCGR3A: odds ratio [OR]=0.621, 95% confidence interval [CI]: 0.513-0.752; FCGR3B: OR=0.594, 95%CI: 0.491-0.719). Conclusion Reduction or deletion of the copy number of the FCGR3A and FCGR3B genes may be a genetic susceptibility factor for the chronicity of HBV infection, but it is not associated with disease progression. -
Key words:
- Hepatitis B virus /
- DNA Copy Number Variations /
- Immunoglobulin G
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表 1 FCGR3A和FCGR3B基因扩增引物
Table 1. Amplification primer information for the FCGR3A and FCGR3B genes
引物 基因片段 染色体 位置
(ref37数据库)1)扩增长度
(样本DNA,
竞争DNA)引物结合区1 引物结合区2 FCGR3-4 FCGR3A Chr1 161599972-161599740 260(+0，-2) GCCAAAAATG TGTGACTCTGAA FCGR3B 161518615-161518383 GGGCCAAGAT GTGCCAGGGA FCGR3-5 FCGR3A Chr1 161514756-161514543 241(+0，-2) TCTTTCAGGCT CTCCTACTTCTG FCGR3B 161596200-161595987 GGCTGTTGCT CAGGGGGCTT 注：1)人类基因组数据库。 
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表 2 慢性HBV感染者不同分组的基线特征
Table 2. Baseline characteristics of different groups of patients with chronic HBV infection
指标 CHB(n=444) LC(n=274) HCC(n=123) 统计值 P值 年龄(岁) 34.02±12.65 49.73±12.46 54.46±12.45 F=202.030 ＜0.001 男/女(例) 350/94 217/57 106/17 χ2=3.429 0.180 ALT(U/L) 71.63±32.98 59.90±22.60 64.19±17.40 F=52.365 ＜0.001 AST(U/L) 63.07±19.96 57.08±21.63 59.86±14.63 F=23.393 ＜0.001 HBV DNA(log10 IU/mL) 6.33±1.42 4.47±1.59 4.07±1.26 H=141.463 ＜0.001 HBeAg[例(%)] χ2=125.255 ＜0.001 阴性 160(36.0) 192(70.1) 101(82.1) 阳性 284(64.0) 82(29.9) 22(17.9)
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表 3 两组HBV感染者FCGR3A和FCGR3B拷贝数分布情况
Table 3. FCGR3A and FCGR3B copy number distribution of HBV infected patients in the two groups
拷贝数 FCGR3A[例(%)] FCGR3B[例(%)] 慢性HBV感染 自限性HBV感染 慢性HBV感染 自限性HBV感染 2 5(0.6) 0 5(0.6) 0 3 93(11.1) 20(6.8) 108(12.8) 17(5.7) 4 551(65.5) 184(62.2) 542(64.5) 186(62.9) 5 162(19.3) 80(27.0) 163(19.4) 79(26.7) 6 28(3.3) 10(3.4) 20(2.4) 12(4.1) 7 1(0.1) 1(0.3) 2(0.2) 1(0.3) 8 1(0.1) 1(0.3) 1(0.1) 1(0.3)
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表 4 两组HBV感染组FCGR3A和FCGR3B拷贝数分布频率差异
Table 4. Differences in frequency distribution of FCGR3A and FCGR3B copy number in the two groups
拷贝数分组 FCGR3A[例(%)] FCGR3B[例(%)] 慢性HBV感染 自限性HBV感染 慢性HBV感染 自限性HBV感染 ≤3 98(11.7) 20(6.8) 113(13.4) 17(5.8) 4 551(65.5) 184(62.1) 542(64.5) 186(62.8) ≥5 192(22.8) 92(31.1) 186(22.1) 93(31.4)
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表 5 慢性HBV感染组不同疾病进展患者FCGR3基因拷贝数分布频率比较
Table 5. Comparison of FCGR3 gene copy number distribution frequency among patients with different disease progression in chronic HBV infection group
基因 拷贝数 CHB LC HCC χ2值 P值 FCGR3A[例(%)] ≤3 54(0.12) 33(0.12) 10(0.08) 3.125 0.537 4 295(0.66) 172(0.63) 85(0.69) ≥5 95(0.22) 69(0.25) 28(0.23) FCGR3B[例(%)] ≤3 70(0.16) 31(0.11) 12(0.10) 5.274 0.260 4 283(0.64) 179(0.65) 80(0.65) ≥5 91(0.20) 64(0.23) 31(0.25)
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表 6 慢性HBV感染组不同HBeAg状态患者FCGR3基因拷贝数分布频率比较
Table 6. Comparison of FCGR3 gene copy number distribution frequency among patients with different HBeAg status in chronic HBV infection group
基因 HBeAg抗原状态 ≤3拷贝 4拷贝 ≥5拷贝 χ2值 P值 FCGR3A[例(%)] 阳性 49(0.12) 254(0.66) 84(0.22) 1.025 0.599 阴性 49(0.11) 297(0.65) 108(0.24) FCGR3B[例(%)] 阳性 56(0.15) 249(0.64) 83(0.21) 0.712 0.701 阴性 57(0.12) 293(0.65) 103(0.23)
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表 7 FCGR3A和FCGR3B CNV与慢性HBV感染后转归的关系
Table 7. Relationship between FCGR3A and FCGR3B gene copy number variation and outcome after chronic HBV infection
基因 变量 B值 SE Wald OR值 95%CI P值 FCGR3A 拷贝数 -0.477 0.098 23.803 0.621 0.513~0.752 ＜0.001 年龄 -0.008 0.004 3.065 0.992 0.984~1.001 0.080 性别 -0.264 0.163 2.620 0.768 0.558~1.057 0.106 FCGR3B 拷贝数 -0.521 0.097 28.649 0.594 0.491~0.719 ＜0.001 年龄 -0.008 0.004 3.013 0.992 0.984~1.001 0.083 性别 -0.264 0.163 2.616 0.768 0.558~1.058 0.106
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[1] WU J, HAN M, LI J, et al. Immunopathogenesis of HBV infection[J]. Adv Exp Med Biol, 2020, 1179: 71-107. DOI: 10.1007/978-981-13-9151-4_4. [2] GRIMM D, HEEG M, THIMME R. Hepatitis B virus: from immunobiology to immunotherapy[J]. Clin Sci (Lond), 2013, 124(2): 77-85. DOI: 10.1042/cs20120169. [3] ISOGAWA M, TANAKA Y. Immunobiology of hepatitis B virus infection[J]. Hepatol Res, 2015, 45(2): 179-189. DOI: 10.1111/hepr.12439. [4] LI F, LI X, ZOU GZ, et al. Association between TLR7 copy number variations and hepatitis B virus infection outcome in Chinese[J]. World J Gastroenterol, 2017, 23(9): 1602-1607. DOI: 10.3748/wjg.v23.i9.1602. [5] PANG Y, GUO W, WANG J, et al. Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA[J]. Oncotarget, 2016, 7(7): 8006-8018. DOI: 10.18632/oncotarget.6895. [6] JIN J, XU H, WU R, et al. Identification of key genes and pathways associated with different immune statuses of hepatitis B virus infection[J]. J Cell Mol Med, 2019, 23(11): 7474-7489. DOI: 10.1111/jcmm.14616. [7] LEJEUNE J, BRACHET G, WATIER H. Evolutionary story of the low/medium-affinity IGg FC receptor gene cluster[J]. Front Immunol, 2019, 10: 1297. DOI: 10.3389/fimmu.2019.01297. [8] BREUNIS WB, van MIRRE E, GEISSLER J, et al. Copy number variation at the fcgr locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B[J]. Hum Mutat, 2009, 30(5): e640-650. DOI: 10.1002/humu.20997. [9] CHEN JY, WANG CM, CHANG SW, et al. Association of FCGR3A and FCGR3B copy number variations with systemic lupus erythematosus and rheumatoid arthritis in taiwanese patients[J]. Arthritis Rheumatol, 2014, 66(11): 3113-3121. DOI: 10.1002/art.38813. [10] LIAN JQ, YANG XF, ZHAO RR, et al. Expression profiles of circulating cytokines, chemokines and immune cells in patients with hepatitis B virus infection[J]. Hepat Mon, 2014, 14(6): e18892. DOI: 10.5812/hepatmon.18892. [11] Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B(2015 version)[J]. J Clin Hepatol, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002.中华医学会肝病学分会, 中华医学会感染病学会分会. 慢性乙型肝炎防治指南(2015年版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002. [12] DU R, LU C, JIANG Z, et al. Efficient typing of copy number variations in a segmental duplication-mediated rearrangement hotspot using multiplex competitive amplification[J]. J Hum Genet, 2012, 57(8): 545-551. DOI: 10.1038/jhg.2012.66. [13] JAKOBSSON M, SCHOLZ SW, SCHEET P, et al. Genotype, haplotype and copy-number variation in worldwide human populations[J]. Nature, 2008, 451(7181): 998-1003. DOI: 10.1038/nature06742. [14] GONZALEZ E, KULKARNI H, BOLIVAR H, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility[J]. Science, 2005, 307(5714): 1434-1440. DOI: 10.1126/science.1101160. [15] ASANO K, MATSUMOTO T, UMENO J, et al. Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis[J]. Inflamm Bowel Dis, 2013, 19(10): 2061-2068. DOI: 10.1097/mib.0b013e318298118e. [16] CHENG FJ, ZHOU XJ, ZHAO YF, et al. Alpha-defensin DEFA1A3 gene copy number variation in Asians and its genetic association study in Chinese systemic lupus erythematosus patients[J]. Gene, 2013, 517(2): 158-163. DOI: 10.1016/j.gene.2013.01.011. [17] ZHOU C, ZHANG W, CHEN W, et al. Integrated analysis of copy number variations and gene expression profiling in hepatocellular carcinoma[J]. Sci Rep, 2017, 7(1): 10570. DOI: 10.1038/s41598-017-11029-y. [18] WIELAND A, SHASHIDHARAMURTHY R, KAMPHORST AO, et al. Antibody effector functions mediated by Fcγ-receptors are compromised during persistent viral infection[J]. Immunity, 2015, 42(2): 367-378. DOI: 10.1016/j.immuni.2015.01.009. [19] HO CH, CHIEN RN, CHENG PN, et al. Aberrant serum immunoglobulin G glycosylation in chronic hepatitis B is associated with histological liver damage and reversible by antiviral therapy[J]. J Infect Dis, 2015, 211(1): 115-124. DOI: 10.1093/infdis/jiu388. [20] WILLCOCKS LC, LYONS PA, CLATWORTHY MR, et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake[J]. J Exp Med, 2008, 205(7): 1573-1582. DOI: 10.1084/jem.20072413. [21] SALMON JE, PRICOP L. Human receptors for immunoglobulin G: Key elements in the pathogenesis of rheumatic disease[J]. Arthritis Rheum, 2001, 44(4): 739-750. DOI: 10.1002/1529-0131(200104)44:4<739::AID-ANR129>3.0.CO;2-O. [22] HUI CK, LEUNG N, YUEN ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase[J]. Hepatology, 2007, 46(2): 395-401. DOI: 10.1002/hep.21724. [23] BEN MKADDEM S, ALOULOU M, BENHAMOU M, et al. Role of FcγRⅢA (CD16) in IVIg-mediated anti-inflammatory function[J]. J Clin Immunol, 2014, 34(Suppl 1): s46-50. DOI: 10.1007/s10875-014-0031-6. [24] BEN MKADDEM S, BENHAMOU M, MONTEIRO RC. Understanding Fc receptor involvement in inflammatory diseases: From mechanisms to new therapeutic tools[J]. Front Immunol, 2019, 10: 811. DOI: 10.3389/fimmu.2019.00811. 期刊类型引用(11)
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