@article{347812bc42314934841b5d0945eb73c8,
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.",
author = "Haralambieva, {Iana H.} and Ovsyannikova, {Inna G.} and Kennedy, {Richard B.} and Larrabee, {Beth R.} and Zimmermann, {Michael T.} and Grill, {Diane E.} and Schaid, {Daniel J.} and Poland, {Gregory A.}",
note = "Funding Information: Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co. Inc., CSL Biotherapies, Avianax, Dynavax, Novartis Vaccines and Therapeutics, Emergent Biosolutions, Adjuvance, Microdermis, Seqirus, NewLink, Protein Sciences, GSK Vaccines, and Sanofi Pasteur. Drs. Poland and Ovsyannikova hold three patents related to measles and vaccinia peptide research. Dr. Kennedy has received funding from Merck Research Laboratories to study waning immunity to measles and mumps after immunization with MMR-II. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. {\textregistered} Funding Information: We thank the Mayo Clinic Vaccine Research Group staff and the study participants. We wish to recognize Julie M. Cunningham and the Mayo Advanced Genomic Technology Center for the genotyping and next generation sequencing efforts, and Nathaniel D. Warner (Division of Biomedical Statistics and Informatics, Mayo Clinic Department of Health Science Research) for his programming assistance and contribution to statistical analysis. We thank Caroline L. Vitse for her editorial assistance with this manuscript. Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R01AI033144 and R37AI048793. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2017, Springer-Verlag Berlin Heidelberg.",
year = "2017",
month = apr,
day = "1",
doi = "10.1007/s00439-017-1768-9",
language = "English (US)",
volume = "136",
pages = "421--435",
journal = "Human genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "4",
}