Correlation of ERAP Gene Polymorphism with Antibody Response Induced by Sequential Immunization of Polio Vaccine
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摘要:
目的 分析内质网氨肽酶（endoplasmic reticulum aminopeptidases，ERAP）基因多态性与脊髓灰质炎疫苗序贯免疫诱导的中和抗体应答的相关性。 方法 选取243名来自广西壮族自治区并完成2剂灭活脊髓灰质炎疫苗和1剂二价口服脊髓灰质炎减毒疫苗接种的壮族受试者，检测免前和基础免疫28 d血清中I、II、III型脊髓灰质炎中和抗体水平，采用TaqMan探针基因分型法对单核苷酸多态性（single nucleotide polymorphism，SNP）进行分型。共选择8个SNP位点，6个ERAP1基因（rs27037、rs27044、rs30187、rs26618、rs26653、rs3734016）和2个ERAP2基因（rs2549782、rs2248374），计算各SNPs的等位基因和基因型频率，分析各SNPs与各型抗体应答的相关性。 结果 在I型脊髓灰质炎抗体应答中，携带rs2549782-G和rs2248374-A等位基因个体抗体几何平均滴度（geometric mean titer，GMT）低于携带rs2549782-T和rs2248374-G等位基因个体[均为（11.590±1.979） vs （11.950±1.895），P = 0.031]；rs2549782基因型GT和rs2248374基因型AG诱导的中和抗体低于rs2549782基因型TT和rs2248374基因型GG[均为（11.741±0.141） vs （12.378±0.157），P = 0.045]。 结论 ERAP2基因多态性可能影响脊髓灰质炎疫苗诱导的抗体水平。 Abstract:Objective To analyze the relationship between endoplasmic reticulum aminopeptidases （ERAP） gene polymorphisms and serum polio antibodies induced by sequential polio vaccine immunization. Methods A total of 243 Zhuang individuals were selected from the Guangxi Zhuang Autonomous Region who received two doses of inactivated polio vaccine and one dose of bivalent oral polio vaccine. Polio-neutralizing antibodies types I, II and III were tested from pre-immunization and 28 days after immunizations, and six ERAP1 and two ERAP2 SNPs were genotyped using TaqMan probe genotyping. The allele frequency and genotype frequency were calculated for each SNP, and the association between the SNPs and the polio antibody response was analyzed. Results It was found that individuals carrying the rs2549782-G andrs2248374-A allele of the ERAP1 gene had lower levels of type I polio-neutralizing antibodies compared to those carrying the T and G alleles, respectively （both of 11.590±1.979 vs 11.950±1.895, Padj = 0.031）. In addition, it was observed that GT and AG genotypes of rs2549782 of rs2248374 exhibited lower GMT type I polio-neutralizing antibodies than those of TT and GG genotypes （both of 11.741±0.141 vs 12.378±0.157, Padj = 0.045）. Conclusion Polio vaccine-induced antibody responses may be associated with ERAP2 gene polymorphism. -
表 1 SNPs的位点信息
Table 1. SNPs information
基因 SNP位点 位置 突变类型 ERAP1 rs27037（G/T） chr5:96758990 intron rs27044（C/G） chr5:96783148 Gln730Glu（Q>E） rs30187（C/T） chr5:96788627 Lys528Arg（K>R） rs26618（T/C） chr5:96795133 Ile276Met（I>M） rs26653（C/G） chr5:96803547 Arg127Pro（R>P） rs3734016（C/T） chr5:96803761 Glu56Lys（E>K） ERAP2 rs2549782（T/G） chr5:96895296 Lys392Asn（K>N） rs2248374（G/A） chr5:96900192 splice region variant 
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表 2 研究对象基本特征（
$\bar x \pm s $ ）Table 2. Basic characteristics of the subjects （
$\bar x \pm s $ ）型别 性别（n） GMT t P I型 男（128） 11.628 ± 2.043 1.350 0.178 女（115） 11.964 ± 1.814 II型 男（128） 6.110 ± 1.806 0.945 0.345 女（115） 6.335 ± 1.910 III型 男（128） 11.409 ± 1.699 1.292 0.198 女（115） 11.675 ± 1.492
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表 3 ERAP基因的SNPs位点等位基因与脊灰中和抗体（GMT）水平的相关性（
$\bar x \pm s $ ）Table 3. Correlation between ERAP SNPs alleles and GMT of neutralizing antibody against poliovirus （
$\bar x \pm s $ ）基因 SNP位点 脊灰抗体型 等位基因 n GMT P ERAP1 rs27037 I G 295 11.860 ± 1.873 0.351 T 191 11.670 ± 2.038 II G 295 6.205 ± 1.765 0.961 T 191 6.233 ± 1.986 III G 295 11.600 ± 1.463 0.838 T 191 11.430 ± 1.801 rs27044 I C 252 11.870 ± 1.913 0.282 G 234 11.700 ± 1.968 II C 252 6.272 ± 1.733 0.416 G 234 6.156 ± 1.937 III C 252 11.620 ± 1.450 0.760 G 234 11.450 ± 1.755 rs30187 I C 249 11.860 ± 1.915 0.338 T 237 11.710 ±1.966 II C 249 6.297 ± 1.784 0.245 T 237 6.131 ± 1.923 III C 249 11.610 ± 1.467 0.815 T 237 11.460 ± 1.738 rs26618 I C 157 11.740 ± 1.902 0.579 T 329 11.810 ± 1.960 II C 157 6.277 ± 1.804 0.497 T 329 6.187 ± 1.878 III C 157 11.650 ± 1.410 0.657 T 329 11.480 ± 1.690 rs26653 I C 247 11.760 ± 1.947 0.657 G 239 11.820 ± 1.936 II C 247 6.114 ± 1.899 0.155 G 239 6.322 ± 1.802 III C 247 11.470 ± 1.725 0.910 G 239 11.800 ± 1.472 rs3734016 I C 428 11.730 ± 1.954 0.077 T 58 12.190 ± 1.792 II C 428 6.170 ± 1.858 0.129 T 58 6.558 ± 1.790 III C 428 11.510 ± 1.634 0.582 T 58 11.720 ± 1.374 ERAP2 rs2549782 I G 221 11.590 ± 1.979 0.031* T 265 11.950 ± 1.895 II G 221 6.187 ± 1.836 0.992 T 265 6.241 ± 1.870 III G 221 11.560 ± 1.578 0.943 T 265 11.510 ± 1.630 rs2248374 I A 221 11.590 ± 1.979 0.031* G 265 11.950 ± 1.895 II A 221 6.187 ± 1.836 0.992 G 265 6.241 ± 1.870 III A 221 11.560 ± 1.578 0.943 G 265 11.510 ± 1.630 *P < 0.05。
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表 4 ERAP基因SNPs的基因型与脊灰I型中和抗体GMT水平的相关性（
$\bar x \pm s $ ）Table 4. Correlation between ERAP SNPs genotypes and GMT of neutralizing antibody against polio type1 （
$\bar x \pm s $ ）ERAP SNP位点 抗体型别 基因型 n GMT P ERAP1 rs27037 I型 GG 86 12.099 ± 1.792 0.109 GT 123 11.535 ± 1.948 TT 34 11.910 ± 2.202 rs27044 I型 CC 58 12.010 ± 2.001 0.563 CG 136 11.750 ± 1.841 GG 49 11.630 ± 2.150 rs30187 I型 CC 56 11.990 ± 2.033 0.626 CT 137 11.750 ± 1.822 TT 50 11.650 ± 2.167 rs26618 I型 CC 20 11.930 ± 1.591 0.672 CT 117 11.670 ± 2.005 TT 106 11.890 ± 1.939 rs26653 I型 CC 57 11.780 ± 2.083 0.830 CG 133 11.730 ± 1.839 GG 53 11.930 ± 2.064 rs3734016 I型 CC 189 11.690 ± 1.968 0.235 CT 50 12.080 ± 1.854 TT 4 12.900 ± 1.286 ERAP2 rs2549782 I型 GG 48 11.600 ± 2.046 0.043* GT 125 11.590 ± 1.942 TT 70 12.280 ± 1.802 rs2248374 I型 AA 48 11.600 ± 2.046 0.043* AG 125 11.590 ± 1.942 GG 70 12.280 ± 1.802 *P < 0.05。
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[1] Tan P L,Jacobson R M,Poland G A,et al. Twin studies of immunogenicity-determining the genetic contribution to vaccine failure[J]. Vaccine,2001,19(17-19):2434-2439. doi: 10.1016/S0264-410X(00)00468-0 [2] Newport M J,Goetghebuer T,Weiss H A,et al. Genetic regulation of immune responses to vaccines in early life[J]. Genes Immun,2004,5(2):122-129. doi: 10.1038/sj.gene.6364051 [3] Neefjes J,Jongsma M L,Paul P,et al. Towards a systems understanding of MHC class I and MHC class II antigen presentation[J]. Nat Rev Immunol,2011,11(12):823-836. doi: 10.1038/nri3084 [4] Vyas J M,Van Der Veen A G,Ploegh H L. The known unknowns of antigen processing and presentation[J]. Nat Rev Immunol,2008,8(8):607-618. doi: 10.1038/nri2368 [5] Yao Y,Liu N,Zhou Z,et al. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations[J]. Hum Immunol,2019,80(5):325-334. doi: 10.1016/j.humimm.2019.02.011 [6] Hattori A,Tsujimoto M. Endoplasmic reticulum aminopeptidases:Biochemistry,physiology and pathology[J]. J Biochem,2013,154(3):219-228. doi: 10.1093/jb/mvt066 [7] Nguyen T T,Chang S C,Evnouchidou I,et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1[J]. Nat Struct Mol Biol,2011,18(5):604-613. doi: 10.1038/nsmb.2021 [8] Evnouchidou I,Birtley J,Seregin S,et al. A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing[J]. J Immunol,2012,189(5):2383-2392. doi: 10.4049/jimmunol.1200918 [9] 傅宇婷,黄腾,英志芳,等. 脊髓灰质炎免疫策略调整进程中不同免疫程序接种效果的比较[J]. 中国生物制品学杂志,2019,32(7):786-793. doi: 10.13200/j.cnki.cjb.002680 [10] 赵志梅,傅宇婷,施红媛,等. Sabin株脊髓灰质炎灭活疫苗与不同剂型Ⅰ型Ⅲ型脊髓灰质炎减毒活疫苗序贯接种的抗体滴度比较[J]. 中华疾病控制杂志,2019,23(4):402-406. doi: 10.16462/j.cnki.zhjbkz.2019.04.007 [11] Liao G,Li R,Li C,et al. Phase 3 Trial of a sabin strain-based inactivated poliovirus vaccine[J]. J Infect Dis,2016,214(11):1728-1734. doi: 10.1093/infdis/jiw433 [12] Liao G,Li R,Li C,et al. Safety and immunogenicity of inactivated poliovirus vaccine made from sabin strains:A phase II,randomized,positive-controlled trial[J]. J Infect Dis,2012,205(2):237-243. doi: 10.1093/infdis/jir723 [13] Chen H,Li L,Weimershaus M,et al. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing[J]. Sci Rep,2016,6(1):28902. doi: 10.1038/srep28902 [14] Stratikos E,Stamogiannos A,Zervoudi E,et al. A role for naturally occurring alleles of endoplasmic reticulum aminopeptidases in tumor immunity and cancer pre-disposition[J]. Front Oncol,2014,4(4):363. [15] Alvarez-Navarro C,López DE Castro J A. ERAP1 structure,function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases[J]. Mol Immunol,2014,57(1):12-21. [16] Stamogiannos A,Koumantou D,Papakyriakou A,et al. Effects of polymorphic variation on the mechanism of endoplasmic reticulum aminopeptidase 1[J]. Mol Immunol,2015,67(2 Pt B):426-435. [17] Coulombe-Huntington J,Lam K C,Dias C,et al. Fine-scale variation and genetic determinants of alternative splicing across individuals[J]. PLoS Genet,2009,5(12):e1000766. doi: 10.1371/journal.pgen.1000766 [18] Cagliani R,Riva S,Biasin M,et al. Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection[J]. Hum Mol Genet,2010,19(23):4705-4714. doi: 10.1093/hmg/ddq401 [19] Biasin M,Sironi M,Saulle I,et al. Endoplasmic reticulum aminopeptidase 2 haplotypes play a role in modulating susceptibility to HIV infection[J]. AIDS,2013,27(11):1697-1706. doi: 10.1097/QAD.0b013e3283601cee [20] Liu S,Cao D,Shen Y,et al. The ERAP gene is associated with HCV chronic infection in a Chinese Han population[J]. Hum Immunol,2017,78(11-12):731-738. doi: 10.1016/j.humimm.2017.10.005 [21] Kuiper J J W,Setten J V,Devall M,et al. Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) uveitis[J]. Hum Mol Genet,2018,27(24):4333-4343. [22] Vanhille D L,Hill L D,Hilliard D D,et al. A novel ERAP2 haplotype structure in a chilean population: Implications for ERAP2 protein expression and preeclampsia risk[J]. Mol Genet Genomic Med,2013,1(2):98-107. doi: 10.1002/mgg3.13 [23] Castro-Santos P,Moro-García M A,Marcos-Fernández R,et al. ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population[J]. Innate Immun,2017,23(5):476-481. doi: 10.1177/1753425917716527 [24] Jiang R,Liu X,Sun X,et al. Immunogenicity and safety of the inactivated poliomyelitis vaccine made from sabin strains in a phase IV clinical trial for the vaccination of a large population[J]. Vaccine,2021,39(9):1463-1471. doi: 10.1016/j.vaccine.2021.01.027 [25] He H,Wang Y,Deng X,et al. Immunogenicity of three sequential schedules with sabin inactivated poliovirus vaccine and bivalent oral poliovirus vaccine in Zhejiang,China: an open-label,randomised,controlled trial[J]. Lancet Infect Dis,2020,20(9):1071-1079. doi: 10.1016/S1473-3099(19)30738-8 [26] Jacobson R M,Poland G A,Vierkant R A,et al. The association of class I HLA alleles and antibody levels after a single dose of measles vaccine[J]. Hum Immunol,2003,64(1):103-109. doi: 10.1016/S0198-8859(02)00741-3 [27] Ovsyannikova I G,Jacobson R M,Vierkant R A,et al. Replication of rubella vaccine population genetic studies:Validation of HLA genotype and humoral response associations[J]. Vaccine,2009,27(49):6926-6931. doi: 10.1016/j.vaccine.2009.08.109 [28] Mineta M,Tanimura M,Tana T,et al. Contribution of HLA class I and class II alleles to the regulation of antibody production to hepatitis B surface antigen in humans[J]. Int Immunol,1996,8(4):525-531. doi: 10.1093/intimm/8.4.525 [29] Hayney M S,Poland G A,Dimanlig P,et al. Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus[J]. Vaccine,1997,15(1):3-6. doi: 10.1016/S0264-410X(96)00133-8 [30] Yucesoy B,Talzhanov Y,Johnson V J,et al. Genetic variants within the MHC region are associated with immune responsiveness to childhood vaccinations[J]. Vaccine,2013,31(46):5381-5391. doi: 10.1016/j.vaccine.2013.09.026 [31] Lankat-Buttgereit B,Tampe R. The transporter associated with antigen processing:Function and implications in human diseases[J]. Physiol Rev,2002,82(1):187-204. doi: 10.1152/physrev.00025.2001 -
