title: Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.
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.
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Iana H
authors.initials: IH
authors.lastname: Haralambieva
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kennedy
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Beth R
authors.initials: BR
authors.lastname: Larrabee
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Grill
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA. poland.gregory@mayo.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000096:biosynthesis*; D000941:Antigens / Q000235:genetics*; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008458:Measles Vaccine / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D057134:Antibodies, Neutralizing; D000941:Antigens; C497857:CD46 protein, human; D003598:Cytoskeletal Proteins; C065888:IFI44 protein, human; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein