title: System-Wide Associations between DNA-Methylation, Gene Expression, and Humoral Immune Response to Influenza Vaccination.
abstract: Failure to achieve a protected state after influenza vaccination is poorly understood but occurs commonly among aged populations experiencing greater immunosenescence. In order to better understand immune response in the elderly, we studied epigenetic and transcriptomic profiles and humoral immune response outcomes in 50-74 year old healthy participants. Associations between DNA methylation and gene expression reveal a system-wide regulation of immune-relevant functions, likely playing a role in regulating a participant's propensity to respond to vaccination. Our findings show that sites of methylation regulation associated with humoral response to vaccination impact known cellular differentiation signaling and antigen presentation pathways. We performed our analysis using per-site and regionally average methylation levels, in addition to continuous or dichotomized outcome measures. The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation. Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity. Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response. Additionally, CpGs that individually predict humoral immune responses are enriched for polycomb-group and FOXP2 transcription factor binding sites. The most robust associations implicate differential methylation affecting gene expression levels of genes with known roles in immunity (e.g. HLA-B and HLA-DQB2) and immunosenescence. We believe our data and analysis strategy highlight new and interesting epigenetic trends affecting humoral response to vaccination against influenza; one of the most common and impactful viral pathogens.
authors.affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.|Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.|Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.|Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Grill
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Iana H
authors.initials: IH
authors.lastname: Haralambieva
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kennedy
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D000368:Aged; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D056724:Immunity, Humoral; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D014611:Vaccination
chemical_list: D007252:Influenza Vaccines