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Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine. Hum Genet 2017 Apr;136(4):421-435

Date

03/16/2017

Pubmed ID

28289848

Pubmed Central ID

PMC5433429

DOI

10.1007/s00439-017-1768-9

Scopus ID

2-s2.0-85015026077 (requires institutional sign-in at Scopus site)   43 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.

Author List

Haralambieva IH, Ovsyannikova IG, Kennedy RB, Larrabee BR, Zimmermann MT, Grill DE, Schaid DJ, Poland GA

Author

Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Antibodies, Neutralizing
Antigens
Child
Cytoskeletal Proteins
Female
Genome-Wide Association Study
Humans
Male
Measles Vaccine
Membrane Cofactor Protein
Polymorphism, Single Nucleotide