Journal Article

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

Jacques Fellay, Petar Scepanovic, Darragh Duffy, Etienne Patin, Laurent Abel, Jacob Bergstedt, Cécile Alanio, Christian Hammer, Bruno Charbit, Christian W. Thorball, Lluis Quintana-Murci, Matthew L. Albert, Flavia Hodel, Nimisha Chaturvedi

2018

Overview

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. Trials registration ClinicalTrials.gov , NCT01699893

• Publisher: Springer Science and Business Media LLC,BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] / [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics / [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE] / [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology / [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity / [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases / Adaptive immunology / Adult / Age / Age; GWAS; HLA; Human genomics; Humoral immunity; Immunoglobulins; Infection; Serology; Sex; Vaccination / Aged / Aging / Aging - immunology / Amino acids / Antibody response / Antigens / Bacterial Infections / Bacterial Infections - immunology / Basic Medicine / Biodiversity / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromosome 2 / Chromosome 6 / Clinical trials / Cytomegalovirus / Epstein-Barr virus / Female / Genetic diversity / Genetic factors / Genetics / Genome-wide association studies / Genomes / Genomics of Infection and Immunity / Genotyping / GWAS / Helicobacter pylori / Hepatitis B / HLA / HLA-D Antigens / HLA-D Antigens - genetics / HLA-D Antigens - immunology / Human Genetics / Human genomics / Human health and pathology / Humans / Humoral immunity / Immune response / Immune response (humoral) / Immunity, Humoral / Immunity, Humoral - genetics / Immunoglobulin A / Immunoglobulin E / Immunoglobulin G / Immunoglobulin M / Immunoglobulins / Immunology / Infection / Infectious diseases / Influenza A / Innate immunity / Life Sciences / Male / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicine / Medicine/Public Health / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / MESH: Adult / MESH: Aged / MESH: Aging/immunology / MESH: Bacterial Infections/immunology / MESH: Female / MESH: HLA-D Antigens/genetics / MESH: HLA-D Antigens/immunology / MESH: Humans / MESH: Immunity, Humoral/genetics / MESH: Male / MESH: Middle Aged / MESH: Polymorphism, Single Nucleotide / MESH: Vaccines/immunology / MESH: Virus Diseases/immunology / Metabolomics / Middle Aged / Mumps / Pathogens / Polymorphism, Single Nucleotide / Populations and Evolution / QH426-470 / Quantitative Methods / R / Rubella / Seroconversion / Serology / Sex / Studies / Systems Biology / Toxoplasma gondii / Vaccination / Vaccines / Vaccines - immunology / Varicella / Virus Diseases / Virus Diseases - immunology