Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine

Iana H. Haralambieva, Inna G. Ovsyannikova, Richard B Kennedy, Beth R. Larrabee, Michael T. Zimmermann, Diane E. Grill, Daniel J Schaid, Gregory A. Poland

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Population-based studies have revealed 2–10% 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 2872 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 = 2.64 × 10−09) and rs2724374 (p value = 3.16 × 10−09) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p value = 1.41 × 10−10) and the missense rs273259 (His73Arg, p value = 2.87 × 10−10) 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.

Original languageEnglish (US)
Pages (from-to)421-435
Number of pages15
JournalHuman Genetics
Volume136
Issue number4
DOIs
StatePublished - Apr 1 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Haralambieva, I. H., Ovsyannikova, I. G., Kennedy, R. B., Larrabee, B. R., Zimmermann, M. T., Grill, D. E., Schaid, D. J., & Poland, G. A. (2017). Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine. Human Genetics, 136(4), 421-435. https://doi.org/10.1007/s00439-017-1768-9