儿童IL6、IL12A/B、IL13基因DNA甲基化与乙型肝炎疫苗低应答水平的关联性

李嘉铃; 苏永健; 董柏青; 吴琪俊; 杨庆利; 陈钦艳; 陈世艺; 谭超; 居昱; 李海

doi:10.16462/j.cnki.zhjbkz.2022.02.021

儿童IL6、IL12A/B、IL13基因DNA甲基化与乙型肝炎疫苗低应答水平的关联性

doi: 10.16462/j.cnki.zhjbkz.2022.02.021

李嘉铃^{1, 2},
苏永健^{1, 2},
董柏青¹,
吴琪俊¹,
杨庆利²,
陈钦艳³,
陈世艺¹,
谭超⁴,
居昱⁵,
李海^{1, 2, ,}

1.
530200 南宁，广西中医药大学公共卫生与管理学院流行病学教研室
2.
530200 南宁，广西中医药大学广西高发传染病中西医结合转化医学重点实验室
3.
530028 南宁，广西壮族自治区疾病预防控制中心病毒性肝炎防制研究重点实验室
4.
541000 桂林，桂林医学院公共卫生学院流行病与卫生统计学教研室
5.
530028 南宁，广西壮族自治区疾病预防控制中心急性传染病防制所

李嘉铃和苏永健为共同第一作者

基金项目:

国家自然科学基金项目 81760604

国家自然科学基金项目 81360443

国家自然科学基金项目 81560546

2013GXNSFBA019194 2013GXNSFBA019194

广西中医药大学研究生教育创新计划资助项目 YCSZ2020020

广西中医药大学研究生教育创新计划资助项目 YCXJ2021030

详细信息

通讯作者:
李海, E-mail: lihai6609@hotmail.com

中图分类号: R181
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- 被引次数: 0
出版历程
- 收稿日期: 2021-03-20
- 修回日期: 2021-07-10
- 网络出版日期: 2022-02-10
- 刊出日期: 2022-02-10

Association between DNA methylation of IL6, IL12A/B, IL13 genes and low response level of hepatitis B vaccine in children

LI Jia-ling^{1, 2},
SU Yong-jian^{1, 2},
DONG Bai-qing¹,
WU Qi-jun¹,
YANG Qing-li²,
CHEN Qin-yan³,
CHEN Shi-yi¹,
TAN Chao⁴,
JU Yu⁵,
LI Hai^{1, 2
, ,}

1.
Department of epidemiology, School of public health and management, Guangxi University of Chinese Medicine, Nanning 530200, China
2.
Guangxi Key Laboratory of Translational Medicine for Treating High-incidence Infectious Diseases with Integrative Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China
3.
Guangxi Key Laboratory for Control and Prevention of Viral Hepatitis, Guangxi Center for Disease Prevention and Control, Nanning 530028, China
4.
Department of epidemiology and health statistics, School of public health, Guilin Medical College, Guilin 541000, China
5.
Department of Emergent Infectious Disease Control and Prevention, Guangxi Center for Disease Prevention and Control, Nanning 530028, China

LI Jia-ling and SU Yong-jian contributed equally to this article

Funds:

National Natural Science Foundation of China 81760604

National Natural Science Foundation of China 81360443

National Natural Science Foundation of China 81560546

Guangxi Natural Science Foundation Project 2013GXNSFBA019194

Funded project of graduate education innovation program of Guangxi University of traditional Chinese Medicine YCSZ2020020

Funded project of graduate education innovation program of Guangxi University of traditional Chinese Medicine YCXJ2021030

More Information

Corresponding author: LI Hai, E-mail: lihai6609@hotmail.com

摘要

摘要: 目的本研究旨在探讨广西壮族自治区汉族儿童白细胞介素6(interleukin 6, IL6)、白细胞介素12A/B(interleukin 12A/B, IL 12A/B)、白细胞介素13(interleukin 13, IL13)基因胞嘧啶-磷酸-鸟苷酸(cytosine-phosphoric-guanylic, CpG)位点DNA甲基化与乙型肝炎疫苗(hepatitis B vaccine, HepB)免疫应答水平的相关性。方法运用非匹配病例对照方法，把来自广西壮族自治区3家医院263名8~9月龄并已接种HepB的汉族儿童作为研究对象，按抗-HBs水平将＜100 mIU/ml儿童作为病例组，≥100 mIU/ml儿童作为对照组。采用多重PCR技术、重亚硫酸盐测序和高通量测序等技术，分析研究IL6、IL12A/B和IL13基因85个位点DNA甲基化情况与HepB免疫应答水平的关系。结果病例组IL6基因117位点、IL12B基因103位点和IL13_2基因167位点甲基化水平均高于对照组，IL12A基因85位点病例组甲基化水平低于对照组(均有P < 0.05)；非条件Logistic回归分析模型分析显示IL6基因117位点和IL13_2基因167位点增加了HepB低应答的风险(OR=1.07, 95% CI: 1.02~1.13; OR=1.04, 95% CI: 1.00~1.07)。结论提示IL6基因117位点和IL13_2基因167位点DNA甲基化修饰可能是广西壮族自治区汉族儿童HepB免疫反应低应答的危险因素。
- DNA甲基化 /
- 细胞因子 /
- 乙型肝炎病毒 /
- 免疫应答水平
Abstract: Objective To explore the correlation between DNA methylation at interleukin 6 (IL6), interleukin 12A/B (IL12A/B), and interleukin 13 (IL13) gene cytosine-phosphoric-guanylic (CpG) sites in Guangxi Han children and the level of hepatitis B vaccine immune response. Methods The non-matched case-control method was used to study 263 Han children from three hospitals in Guangxi who were 8-9 months old and had been vaccinated with HepB. According to the research object, subjects with anti-HBs level < 100 mIU/ml were selected to the case group, and subjects with anti-HBs ≥100 mIU/ml was chosen to the control group. Using multiplex PCR technology, bisulfite sequencing, high-throughput sequencing and other technologies, the relationship between DNA methylation at 85 sites of IL6, IL12A/B and IL13 genes and the level of HepB immune response were analyzed and studied. Results The average methylation levels of IL6 gene 117, IL12B gene 103, and IL13_2 gene 167 of the case group was higher than those of the control group, and the average methylation level of IL12A gene 85 of the case group was lower than that of the control group (all P < 0.05). Unconditional Logistic regression showed that IL6 gene 117 and IL13_2 gene 167 increased the risk of low HepB response (OR=1.07, 95% CI: 1.02-1.13; OR=1.04, 95% CI: 1.00-1.07). Conclusion It is suggested that the DNA methylation modification of IL6 gene 117 site and IL13_2 gene 167 site may be the risk factor of the low response of HepB immune response in Guangxi Han children.
- DNA methylation /
- Cytokine /
- Hepatitis B vaccine /
- Immune response level

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表 1 研究对象基本情况抗-HBs应答水平分布[n(%)]

Table 1. Basic information of among subjects Anti-HBs response level distribution among subjects [n(%)]

免疫应答	性别		月龄(月)		合计
免疫应答	男	女	8	9	合计
无、低应答	90(39.5)	14(40.0)	12(27.9)	92(41.8)	104(39.5)
正常、高应答	138(60.5)	21(60.0)	31(72.1)	128(58.2)	159(60.5)
合计	228(100.0)	35(100.0)	43(100.0)	220(100.0)	263(100.0)
Z值	-0.67		-1.76
P值	0.501		0.079

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表 2 病例组和对照组IL6、IL12A/B与IL13基因DNA甲基化水平[M(IR)]

Table 2. DNA methylation levels of IL6, IL12A/B and IL13 gene were compared between case and control group [M(IR)]

基因	CpG位置	合计(N=263)	病例组(n=104)	对照组(n=159)	Z值	FDR值	P值
IL6_1	49	0.775(0.055)	0.773(0.056)	0.776(0.051)	0.14	0.976	0.554
	85	0.775(0.061)	0.781(0.049)	0.771(0.065)	-1.19	0.785	0.116
	103	0.764(0.072)	0.771(0.054)	0.760(0.077)	-1.11	0.785	0.132
	117	0.796(0.072)	0.807(0.069)	0.789(0.076)	-1.99	0.557	0.023
	119	0.766(0.072)	0.773(0.067)	0.762(0.080)	-0.75	0.813	0.225
IL6_2	69	0.556(0.127)	0.547(0.157)	0.563(0.117)	0.15	0.976	0.561
	103	0.323(0.140)	0.316(0.124)	0.328(0.150)	-0.27	0.900	0.394
	121	0.416(0.138)	0.411(0.112)	0.419(0.153)	-0.42	0.900	0.339
	132	0.371(0.140)	0.360(0.139)	0.379(0.145)	-1.35	0.785	0.088
	135	0.449(0.156)	0.435(0.133)	0.458(0.150)	-0.91	0.785	0.182
	174	0.590(0.139)	0.575(0.125)	0.600(0.143)	-1.33	0.785	0.091
	192	0.582(0.121)	0.588(0.126)	0.578(0.118)	0.32	0.976	0.626
	197	0.776(0.112)	0.777(0.115)	0.776(0.108)	1.03	0.993	0.848
	203	0.646(0.125)	0.637(0.118)	0.652(0.133)	-0.52	0.853	0.303
	220	0.483(0.124)	0.472(0.134)	0.490(0.131)	-0.57	0.848	0.284
	228	0.553(0.133)	0.554(0.129)	0.552(0.139)	0.74	0.976	0.772
IL12A	19	0.009(0.014)	0.010(0.015)	0.009(0.013)	1.05	0.993	0.853
	23	0.007(0.012)	0.007(0.012)	0.007(0.012)	-0.30	0.900	0.382
	36	0.007(0.011)	0.008(0.011)	0.006(0.011)	-1.54	0.785	0.061
	38	0.007(0.011)	0.007(0.012)	0.007(0.011)	-0.14	0.918	0.443
	49	0.006(0.009)	0.006(0.009)	0.005(0.009)	-0.17	0.912	0.433
	58	0.007(0.010)	0.007(0.010)	0.006(0.009)	0.90	0.979	0.815
	74	0.007(0.010)	0.006(0.011)	0.008(0.010)	-1.07	0.785	0.142
	85	0.006(0.010)	0.005(0.009)	0.007(0.010)	-1.77	0.754	0.039
	88	0.005(0.007)	0.004(0.007)	0.005(0.008)	-1.08	0.785	0.141
	94	0.010(0.010)	0.010(0.010)	0.009(0.010)	0.29	0.976	0.612
	99	0.007(0.010)	0.007(0.010)	0.006(0.010)	2.26	1.000	0.988
	104	0.004(0.007)	0.004(0.008)	0.005(0.007)	1.94	1.000	0.974
	110	0.005(0.008)	0.005(0.009)	0.004(0.007)	-1.05	0.785	0.148
	114	0.007(0.011)	0.008(0.012)	0.007(0.010)	-0.96	0.785	0.168
	123	0.006(0.009)	0.005(0.008)	0.006(0.010)	-0.29	0.900	0.385
	135	0.008(0.013)	0.009(0.014)	0.008(0.012)	-0.56	0.848	0.288
	141	0.007(0.010)	0.006(0.009)	0.007(0.010)	-1.60	0.785	0.055
	144	0.011(0.011)	0.011(0.010)	0.010(0.011)	0.69	0.976	0.754
	153	0.008(0.012)	0.007(0.011)	0.008(0.014)	-1.13	0.785	0.128
	155	0.006(0.009)	0.005(0.009)	0.006(0.009)	0.50	0.976	0.690
	160	0.008(0.012)	0.008(0.011)	0.008(0.013)	-0.22	0.900	0.413
	164	0.011(0.010)	0.011(0.012)	0.011(0.009)	0.10	0.968	0.540
	169	0.012(0.012)	0.011(0.017)	0.012(0.011)	-0.49	0.859	0.311
	173	0.008(0.011)	0.008(0.013)	0.007(0.011)	1.18	0.997	0.880
	181	0.010(0.014)	0.009(0.013)	0.011(0.010)	-0.79	0.813	0.215
IL12B	22	0.013(0.010)	0.013(0.010)	0.013(0.010)	0.75	0.976	0.772
	24	0.010(0.009)	0.010(0.009)	0.009(0.008)	-1.08	0.785	0.141
	35	0.035(0.015)	0.033(0.014)	0.036(0.016)	-1.36	0.785	0.087
	40	0.010(0.008)	0.010(0.008)	0.010(0.008)	0.64	0.976	0.740
	42	0.010(0.008)	0.010(0.009)	0.009(0.006)	-0.57	0.848	0.284
	53	0.038(0.018)	0.038(0.019)	0.038(0.019)	1.20	1.000	0.885
	58	0.029(0.013)	0.029(0.013)	0.028(0.014)	0.29	0.976	0.616
	60	0.024(0.011)	0.025(0.010)	0.024(0.011)	-0.72	0.813	0.237
	71	0.011(0.010)	0.010(0.010)	0.011(0.009)	0.63	0.976	0.737
	78	0.009(0.007)	0.009(0.006)	0.009(0.008)	0.47	0.976	0.680
IL12B
	94	0.008(0.007)	0.008(0.006)	0.008(0.008)	-0.58	0.848	0.280
	96	0.008(0.008)	0.008(0.008)	0.008(0.009)	1.72	1.000	0.957
	103	0.009(0.008)	0.010(0.008)	0.009(0.007)	-1.67	0.785	0.047
	108	0.008(0.008)	0.009(0.008)	0.008(0.008)	-1.14	0.785	0.127
	113	0.006(0.006)	0.007(0.006)	0.006(0.007)	-0.87	0.785	0.193
	123	0.007(0.006)	0.007(0.006)	0.006(0.006)	-1.00	0.785	0.160
	126	0.006(0.006)	0.007(0.007)	0.006(0.007)	-1.21	0.785	0.112
	143	0.011(0.009)	0.013(0.010)	0.011(0.009)	-1.23	0.785	0.110
	155	0.013(0.009)	0.013(0.010)	0.013(0.008)	0.39	0.976	0.651
	170	0.014(0.010)	0.013(0.010)	0.014(0.010)	-0.35	0.900	0.365
	194	0.010(0.009)	0.010(0.009)	0.010(0.009)	0.87	0.979	0.808
IL13_1	60	0.906(0.041)	0.904(0.043)	0.906(0.038)	0.82	0.977	0.793
	64	0.925(0.033)	0.926(0.031)	0.924(0.034)	1.55	1.000	0.940
	66	0.892(0.046)	0.893(0.045)	0.892(0.046)	2.26	1.000	0.988
	76	0.912(0.038)	0.912(0.038)	0.912(0.037)	0.57	0.976	0.717
	104	0.909(0.038)	0.911(0.037)	0.908(0.039)	0.91	0.981	0.819
	113	0.908(0.037)	0.910(0.041)	0.906(0.033)	-0.38	0.900	0.354
	120	0.865(0.049)	0.867(0.048)	0.864(0.050)	0.22	0.976	0.588
	154	0.857(0.052)	0.859(0.055)	0.856(0.051)	0.31	0.976	0.622
	165	0.897(0.039)	0.900(0.033)	0.895(0.041)	-0.84	0.785	0.199
	195	0.884(0.044)	0.887(0.048)	0.882(0.042)	-0.40	0.900	0.346
	199	0.877(0.044)	0.877(0.043)	0.877(0.045)	1.39	1.000	0.918
	211	0.887(0.041)	0.888(0.049)	0.886(0.037)	0.77	0.976	0.779
IL13_2	34	0.109(0.054)	0.108(0.055)	0.109(0.060)	0.70	0.976	0.760
	39	0.078(0.041)	0.078(0.038)	0.077(0.044)	0.41	0.976	0.660
	43	0.137(0.067)	0.136(0.075)	0.138(0.064)	-0.08	0.940	0.468
	48	0.139(0.068)	0.138(0.076)	0.140(0.064)	0.39	0.976	0.653
	56	0.130(0.059)	0.131(0.058)	0.130(0.060)	2.55	1.000	0.995
	58	0.060(0.037)	0.059(0.040)	0.061(0.035)	-0.15	0.918	0.441
	109	0.078(0.042)	0.078(0.041)	0.079(0.043)	0.51	0.976	0.696
	123	0.057(0.035)	0.055(0.032)	0.058(0.038)	0.69	0.976	0.755
	127	0.114(0.065)	0.112(0.061)	0.115(0.066)	0.86	0.977	0.805
	162	0.376(0.161)	0.372(0.157)	0.378(0.169)	0.51	0.976	0.695
	167	0.210(0.124)	0.225(0.108)	0.201(0.123)	-2.37	0.489	0.009

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表 3 IL6、IL12A/B与IL13基因DNA甲基化水平与HepB应答水平Logistic回归分析模型分析

Table 3. Logistic regression analysis of IL6, IL12A/B and IL13 gene DNA methylation and HepB response level

基因	位置	灵敏度(%)	特异度(%)	准确度(%)	AUC	OR(95% CI)值	P值
IL6_1	117	81.0	33.3	51.5	0.580	1.07(1.02~1.13)	0.010
IL12A	85	69.4	51.5	58.2	0.574	0.70(0.47~1.05)	0.084
IL12B	103	65.0	51.2	56.5	0.573	1.34(0.91~1.99)	0.143
IL13_2	167	74.0	44.1	55, 6	0.596	1.04(1.00~1.07)	0.024

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