Immunity & infection
Healthy humans are regularly infected with pathogens that have the ability to persist through life. Our hypothesis is that host factors influence (i) the rate of seroconversion upon exposure, (ii) the intensity and characteristics of immune responses. To test this, we used a systems biology approach, integrating serological testing, genome-wide association studies (GWAS) and extensive immunophenotyping in 1000 healthy individuals recruited by the Milieu Interieur Consortium. Blood composition was assessed by flow cytometry. Serums were used for measurement of IgGs against (i) persistent or recurrent viruses - Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus 1 & 2 (HSV-1 & 2), Varicella zoster virus (VZV), and Influenza A virus; (ii) persistent bacteria - Helicobacter pylori (HP), (iii) persistent parasite - Toxoplasma gondii, and (iv) pathogens targeted by vaccines - Measles, Mumps, Rubella, and Hepatitis B virus. Illumina Omni Express and HumanExome arrays were used for genotyping. After imputation with IMPUTE2, logistic or linear regressions were performed to detect associations between 5 million human polymorphisms, immune phenotypes and antibody responses. No genome-wide significant associations were found for serostatus. In contrast, genome-wide significant associations (P < 5*10-8) were observed within the MHC locus on chromosome 6 for the levels of IgG mounted against EBV and Rubella. By imputing classical HLA alleles and amino-acids, we found that these associations correspond to variations in amino acid composition of HLA-DRβ1 and HLA-DPβ1 molecules respectively. Together, our results provide new possible insights into mechanisms determining response to persistent pathogens, and encourage further genetic and functional work.