Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

Petar Scepanovic, Cécile Alanio, Christian Hammer, Flavia Hodel, Jacob Bergstedt, Etienne Patin, Christian W. Thorball, Nimisha Chaturvedi, Bruno Charbit, Laurent Abel, Lluis Quintana-Murci, Darragh Duffy, Matthew L. Albert, Jacques Fellay, Andres Alcover, Hugues Aschard, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline DemangelLudovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Odile Gelpi, Ivo Gomperts-Boneca, Milena Hasan, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Marie Noëlle Ungeheuer, Kalla Astrom, Serge Hercberg, Mathilde Touvier, Olivier Lantz, Vassili Soumelis, Stanislas Pol, Antonio Rausell, Eric Tartour, Antoine Toubert

Research output: Contribution to journalArticlepeer-review


Background: 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 evaluated 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 1000 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 and 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: We identified age and sex as important determinants of humoral immunity, 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 leukocyte 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 demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. 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.

Original languageEnglish
Article number59
JournalGenome Medicine
Issue number1
Publication statusPublished - 2018 Jul 27

Subject classification (UKÄ)

  • Medical Genetics


  • Age
  • GWAS
  • HLA
  • Human genomics
  • Humoral immunity
  • Immunoglobulins
  • Infection
  • Serology
  • Sex
  • Vaccination


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