每年接种疫苗是预防流感感染的最有效方法。到目前为止,一系列研究证明了遗传变异在调节流感疫苗抗体反应中的作用。然而,在中国人口中,遗传因素与流感疫苗接种应答之间的关系尚未通过全基因组关联研究(GWAS)阐明.
总共招募了1,968名中国血统的健康志愿者,其中1,582人可用于随后的两阶段分析。在发现阶段,根据我们的纳入标准,选择1,582名受试者中的123名作为第1组,并接受全基因组测序以鉴定潜在的变体和基因。在验证阶段,在第2组中的481名受试者中选择通过GWAS鉴定的29个候选变体用于进一步验证。此外,我们还分析了我们研究中以前发表的报告中的9种变异.
多因素logistic回归分析显示,与ZBTB46rs2281929的TT基因型相比,TC+CC基因型在调整性别和年龄后,对流感疫苗接种低反应性的风险较低(第2组:P=7.75E-05,OR=0.466,95CI=0.319-0.680;联合组:P=1.18E-06,OR=0.423,95CI=0.299-0.299-在合并组中,与GG基因型相比,IQGAP2rs2455230GC+CC基因型与对流感疫苗接种的低反应性风险较低相关(P=8.90E-04,OR=0.535,95CI=0.370-0.774),但两组差异无统计学意义(P=0.008)。具有ZBTB46rs2281929TT基因型的受试者针对H1N1,H3N2和B的抗体倍数升高均显着低于具有TCCC基因型的受试者(P<0.001)。与IQGAP2rs2455230GC+CC载波相比,GG携带者对H1N1(P=0.001)和B(P=0.032)的抗体升高倍数较低。rs2455230的GG基因型倾向于与针对H3N2的较低抗体倍数升高相关(P=0.096),但差异无统计学意义。在我们的研究中,先前发表的报告中的9个SNP与对流感疫苗的血清学反应之间没有发现相关性。
我们的研究确定了两个新的候选错义变体,ZBTB46rs2281929和IQGAP2rs2455230与中国人群对流感疫苗接种的免疫反应有关。识别这些变异将为未来的研究提供更多证据,并改善个性化的流感疫苗接种计划。
Annual vaccination is the most effective prevention of influenza infection. Up to now, a series of studies have demonstrated the role of genetic variants in regulating the antibody response to influenza vaccine. However, among the Chinese population, the relationship between genetic factors and the responsiveness to influenza vaccination has not been clarified through genome-wide association study (GWAS).
A total of 1,968 healthy volunteers of Chinese descent were recruited and 1,582 of them were available for the subsequent two-stage analysis. In the discovery stage, according to our inclusion criteria, 123 of 1,582 subjects were selected as group 1 and received whole-genome sequencing to identify potential variants and genes. In the verification stage, 29 candidate variants identified by GWAS were selected for further validation in 481 subjects in group 2. Besides, we also analyzed nine variants from previously published reports in our study.
Multivariate logistic regression analysis showed that compared with the TT genotype of
ZBTB46 rs2281929, the TC + CC genotype was associated with a lower risk of low responsiveness to influenza vaccination adjusted for gender and age (Group 2: P = 7.75E-05, OR = 0.466, 95%CI = 0.319-0.680; Combined group: P = 1.18E-06, OR = 0.423, 95%CI = 0.299-0.599). In the combined group, IQGAP2 rs2455230 GC + CC genotype was correlated with a lower risk of low responsiveness to influenza vaccination compared with the GG genotype (P = 8.90E-04, OR = 0.535, 95%CI = 0.370-0.774), but the difference was not statistically significant in group 2 (P = 0.008). The antibody fold rises of subjects with
ZBTB46 rs2281929 TT genotype against H1N1, H3N2,and B were all significantly lower than that of subjects with TC + CC genotype (P < 0.001). Compared with IQGAP2 rs2455230 GC + CC carriers, GG carriers had lower antibody fold rises to H1N1 (P = 0.001) and B (P = 0.032). The GG genotype of rs2455230 tended to be correlated with lower antibody fold rises (P = 0.096) against H3N2, but the difference was not statistically significant. No correlation was found between nine SNPs from previously published reports and the serological response to influenza vaccine in our study.
Our study identified two novel candidate missense variants,
ZBTB46 rs2281929 and IQGAP2 rs2455230, were associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide more evidence for future research and improve the individualized influenza vaccination program.