TLR基因多态性对广西汉族儿童乙型肝炎疫苗初次免疫应答水平的影响

李海; 吕应楠; 杨庆利; 居昱; 陈钦艳; 谭超; 董柏青; 吴琪俊

doi:10.16462/j.cnki.zhjbkz.2019.04.006

TLR基因多态性对广西汉族儿童乙型肝炎疫苗初次免疫应答水平的影响

doi: 10.16462/j.cnki.zhjbkz.2019.04.006

李海^{1, 2, 3},
吕应楠⁴,
杨庆利^{2, 3},
居昱⁴,
陈钦艳^{2, 3},
谭超⁴,
董柏青¹,
吴琪俊^1, ,

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.
530028 南宁, 广西壮族自治区疾病预防控制中心病毒性肝炎防治研究重点实验室
3.
530028 南宁, 广西病毒性肝炎防治研究重点实验室
4.
530021 南宁, 广西医科大学公共卫生学院劳动卫生与环境卫生学教研室
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
6.
541100 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

基金项目:

国家自然科学基金项目 81360443

国家自然科学基金项目 81560546

广西自然科学基金项 2013GXNSFBA019194

详细信息

通讯作者:
吴琪俊, E-mail: gxwqj2017@163.com

中图分类号: R181
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出版历程
- 收稿日期: 2018-09-12
- 修回日期: 2019-01-26
- 刊出日期: 2019-04-10

Effect of TLR gene polymorphisms on primary immune response to hepatitis B vaccine in Han children of Guangxi

LI Hai^{1, 2, 3},
LV Ying-nan⁴,
YANG Qing-li^{2, 3},
JU Yu⁴,
CHEN Qin-yan^{2, 3},
TAN Chao⁴,
DONG Bai-qing¹,
WU Qi-jun^{1
, ,}

1.
Department of Epidemiology, School of Public Health and Management, Guangxi University of Chinese Medicine, Nanning 530200, China
2.
Laboratory for the Control and Prevention of Viral Hepatitis, Guangxi Centre for Disease Prevention and Control, Nanning 530028, China
3.
Guangxi Key Laboratory for the Control and Prevention of Viral Hepatitis, Nanning 530028, China
4.
Department of Emergent infectious disease prevention and control, Guangxi Centre for Disease Prevention and Control, Nanning 530028, China
5.
Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, China
6.
Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, Guilin 541100, China

Funds:

National Natural Science Foundation of China 81360443

National Natural Science Foundation of China 81560546

Guangxi Natural Science Foundation 2013GXNSFBA019194

More Information

Corresponding author: WU Qi-jun, E-mail: gxwqj2017@163.com

摘要

摘要: 目的探讨Toll样受体(toll-like receptors，TLR)基因多态性与广西汉族儿童乙型肝炎(以下简称乙肝)疫苗初次免疫应答水平的关联。方法收集2014-2016年到广西自治区妇幼保健院、南宁市妇幼保健院儿科就诊的8~9月龄汉族儿童513例为研究对象。采集外周血标本，采用微粒子酶免疫法检测乙肝血清标志物"两对半"，用套式聚合酶链式反应法检测乙肝病毒DNA，应用SNPscanTM多重SNP分型技术检测TLR基因10个位点的基因多态性。采用非条件Logistic回归分析TLR等位基因、基因型与儿童乙肝疫苗免疫后应答的关联。结果 TLR3基因rs13126816的基因多态性与广西汉族儿童初次乙肝疫苗免疫后应答情况有关(OR=1.79，95% CI：1.11~2.89，P=0.018)；A/A基因型[238.04(519.75) mIU/L]和G/A基因型[347.96(619.68) mIU/L]儿童的乙肝病毒表面抗体(hepatitis B surface antibody，抗-HBs)水平明显低于G/G基因型[489.08(854.76) mIU/L]的儿童，差异均有统计学意义(均有P < 0.05)；携带等位基因A[317.20(608.72) mIU/L]儿童的抗-HBs水平也明显低于携带等位基因G[457.01(852.66) mIU/L]的儿童，差异有统计学意义(Z=-3.055，P < 0.05)。TLR基因其余位点均与乙肝疫苗免疫应答无关(均有P>0.05)。结论 TLR3基因rs13126816位点等位基因A可能是汉族儿童产生初次乙肝疫苗免疫低应答的影响因素。
- Toll样受体 /
- 单核苷酸多态性 /
- 乙型肝炎疫苗 /
- 免疫应答
Abstract: Objective To explore the association between Toll-like receptors(TLR) gene polymorphisms and the primary immune response level to Hepatitis B Vaccine in Han children in Guangxi. Methods A total of 513 Han children aged 8-9 months were collected from the department of pediatrics in the Maternal and Child Hospital of Guangxi Zhuang Autonomous Region and Nanning Maternal and Child Health Hospital from 2014 to 2016. Peripheral venous blood of each study object was collected to detect HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc and HBV DNA. The polymorphisms of 10 sites of TLR gene were detected by SNPscanTM multiple SNP typing techniques. The association between allele, genotype of TLR gene and anti-HBs levels were analyzed by non-conditional logistic regression. Results The genetic polymorphism of TLR3 gene rs13126816 was related to immune response after primary Hepatitis B immunization in Han children in Guangxi (OR=1.79, 95% CI: 1.11-2.89, P=0.018). The anti-HBs level of children with A/A genotype[238.04(519.75) mIU/L] and G/A genotype[347.96(619.68) mIU/L] were significantly lower than those with G/G genotype[489.08(854.76) mIU/L], and the differences were statistically significant (all P < 0.05). Anti-HBs level of children carrying allele A[317.20(608.72) mIU/L] was significantly lower than those carrying allele G[457.01(852.66) mIU/L], and the difference was statistically significant (Z=-3.055, P < 0.05). The rest of the TLR genes were not related to the immune response of Hepatitis B Vaccine (all P>0.05). Conclusions The allele A of TLR3 gene rs13126816 may be the influencing factor for the low response of primary immune response to Hepatitis B Vaccine in Han children.
- Toll like receptor /
- Single-nucleotide Polymorphism(SNPs) /
- Hepatitis B vaccine /
- Immune response

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图 1 TLR3基因rs13126816等位基因的抗-HBs水平分布图

Figure 1. Anti-HBs profile of TLR3 gene rs13126816 allele

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表 1 本次研究分析的TLR基因10个位点

Table 1. Ten sites of TLR gene for SNPs analysis

基因	位点	区域
TLR2	rs3804100	exonic
TLR3	rs11721827	intronic
	rs3775296	UTR5
	rs13126816	intronic
	rs7657186	intronic
	rs3775292	intronic
	rs3775291	exonic
	rs7668666	intronic
TLR4	rs1927911	intronic
	rs11536889	UTR3

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表 2 研究对象的基本情况

Table 2. Base line data of study subjects

变量	合计(n=513)	男童(n=395)	女童(n=118)	t/Z/χ²值	P值
年龄(月，x±s)	8.89±0.31	8.90±0.31	8.88±0.33	0.457^a	0.648
抗-HBs水平[mIU/L，M(IR)]	403.40(856.53)	363.94(869.87)	544.31(802.48)	-1.217^b	0.224
抗-HBs构成[n(%)]				9.416^c	0.024
无应答	17(3.31)	9(2.28)	8(6.78)
低应答	88(17.16)	75(18.99)	13(11.01)
正常应答	276(53.80)	208(52.66)	68(57.63)
高应答	132(25.73)	103(26.07)	29(24.58)
注：^a不同性别年龄比较，资料服从正态分布，采用两独立样本t检验(计算t值)；^b不同性别抗-HBs水平比较，资料不服从正态分布，采用Mann-Whitney U检验(计算Z值)；^c不同性别抗-HBs构成比较，为单向有序行列表计数资料，采用Kruskal-Wallis H检验(计算χ²值)

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表 3 TLR基因各SNPs与抗-HBs关联Logistic回归分析

Table 3. Analysis for the association between SNPs of TLR gene and anti-HBs levels by Logistic regression

基因	位点	染色体	物理位置	次等位基因/主要等位基因	基因型AA/AB/BB	最小等位基因频率	OR(95% CI)值	P值
TLR2	rs3804100	4	154625409	C/T	13/67/140	0.211 4	0.95(0.60~1.49)	0.814
TLR3	rs11721827	4	186991137	C/A	1/44/175	0.104 5	0.85(0.44~1.64)	0.631
	rs7657186	4	186994039	A/G	10/69/141	0.202 3	0.81(0.50~1.30)	0.374
	rs13126816	4	186994178	A/G	10/66/144	0.195 5	1.79(1.11~2.89)	0.018
	rs3775296	4	186997767	A/C	19/85/116	0.279 5	0.90(0.59~1.37)	0.619
	rs3775292	4	187003025	C/G	6/70/144	0.186 4	0.89(0.53~1.47)	0.644
	rs3775291	4	187004074	T/C	28/92/100	0.336 4	1.32(0.89~1.95)	0.169
	rs11536879	9	120472211	G/A	4/46/170	0.122 7	0.75(0.41~1.37)	0.344
	rs1927907	9	120472764	T/C	5/58/157	0.154 5	0.99(0.58~1.68)	0.966
TLR4	rs1927911	9	120470054	A/G	18/91/111	0.288 6	0.90(0.59~1.38)	0.626
	rs11536889	9	120478131	C/G	22/98/100	0.322 7	1.01(0.66~1.53)	0.970

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表 4 TLR3基因rs13126816基因型抗-HBs水平的分布情况[M(IR)]

Table 4. The distribution of anti-HBs levels of TLR3 gene rs13126816 allele[M(IR)]

抗-HBs水平(mIU/L)	基因型			χ²值	P值	等位基因		χ²值	P值
抗-HBs水平(mIU/L)	A/A (n=35)	G/A (n=182)	G/G (n=296)	χ²值	P值	A (n=252)	G (n=774)	χ²值	P值
男童(n=395)	245.69(561.53) ^a	305.74(633.47) ^a	451.18(860.66)	8.124	0.017	290.01(552.69)	408.94(865.33)	-2.943	0.003
女童(n=118)	227.11(568.16)	525.70(614.60)	603.29(819.34)	1.410	0.494	463.58(608.73)	557.34(818.34)	-1.047	0.295
合计(n=513)	238.04(519.75)^a	347.96(619.68) ^a	489.08(854.76)	8.751	0.013	317.20(608.72)	457.01(852.66)	-3.055	0.002
注：^a与G/G相比，P＜0.05。

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