Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.
Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.
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CD46 和 IFI44L 基因变异与麻疹疫苗中和抗体反应的全基因组关联。
DOI：
10.1007/s00439-017-1768-9
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发表时间：
2017-04
期刊：
影响因子：
5.3
通讯作者：
Poland GA
中科院分区：
文献类型：
--
作者：
Haralambieva IH;Ovsyannikova IG;Kennedy RB;Larrabee BR;Zimmermann MT;Grill DE;Schaid DJ;Poland GA
基于人群的研究表明，即使在两次接种疫苗后，麻疹疫苗的失败率仍为2%至10%。虽然这背后的机制尚不清楚，但我们假设宿主遗传因素可能参与其中。我们在2872名受试者的联合样本中进行了麻疹特异性中和抗体和IFNγ ELISPOT反应的全基因组关联研究。我们确定了两个不同的染色体1区域（以前与mmr相关的发热性癫痫发作相关），与疫苗诱导的麻疹中和抗体滴度相关。麻疹病毒受体编码CD46基因的1q32区包含20个显著snp，包括内含子rs2724384 （p值= 2.64 × 10−09）和rs2724374 (p值= 3.16 × 10−09)snp。在IFI44L的1q31.1区域包含9个显著snp，包括内含子rs1333973 （p值= 1.41 × 10−10）和错义rs273259 (His73Arg， p值= 2.87 × 10−10)snp。利用mRNA-Seq数据和RT-PCR分析外显子使用的差异表明，rs2724374小G等位基因参与CD46 STP区域外显子B跳变，导致CD46亚型变短。我们的研究揭示了与麻疹特异性体液免疫相关的常见CD46和IFI44L snp，并强调了剪接/病毒细胞受体异构体的选择性使用作为解释麻疹活疫苗后免疫反应个体间差异的机制的重要性。
Population-based studies have revealed 2 to 10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2,872 subjects. We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p-value = 2.64x10−09) and rs2724374 (p-value = 3.16x10−09) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p-value = 1.41x10−10) and the missense rs273259 (His73Arg, p-value = 2.87x10−10) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.