RT Journal Article
SR Electronic
T1 Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 254706
DO 10.1101/254706
A1 Petar Scepanovic
A1 Cécile Alanio
A1 Christian Hammer
A1 Flavia Hodel
A1 Jacob Bergstedt
A1 Etienne Patin
A1 Christian W. Thorball
A1 Nimisha Chaturvedi
A1 Bruno Charbit
A1 Laurent Abel
A1 Lluis Quintana-Murci
A1 Darragh Duffy
A1 Matthew L. Albert
A1 Jacques Fellay
A1 The Milieu Intérieur Consortium
YR 2018
UL http://biorxiv.org/content/early/2018/01/27/254706.abstract
AB Introduction Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluate the impact of intrinsic (age and sex), environmental and genetic factors on the variability of humoral response to common pathogens and vaccines.Methods We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age‐ and sex-stratified cohort of 1,000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 & 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests.Results and discussion We identified age and sex as important determinants of humoral response, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leucocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.Conclusions Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrate that age, sex and specific human genetic variants contribute to inter-individual variability in humoral response. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.