Genetic determinants of healthy human immune variance: from humoral response to microbiome diversity

Identifying the drivers of the observed interindividual variability of the human immune system is crucial to our understanding of infectious and immune-mediated diseases. The contribution of genetic and non-genetic factors to immunological differences between humans remains largely undefined. The Milieu Intérieur Consortium has established a 1000-person healthy population-based cohort (evenly stratified by sex and age), which represents an unparalleled opportunity for assessing the determinants of human immunologic variance.

In this thesis, three population-based studies are presented, all benefiting from the samples and data collected by investigators of the Milieu Intérieur Consortium. Human genome-wide genotyping data, more than 100 environmental, lifestyle and physiological variables, and their combination have been tested for their impact on multiple immune phenotypes. Firstly, we identified the respective contributions of age, sex, and genetics to humoral responses to vaccination and persistent viral infection. We observed that specific variants in the human leukocyte antigen (HLA) region are the strongest genetic determinant of antibody response to common antigens. In the second study, investigation of 166 immuno-phenotypes revealed 15 genetic loci associated with variation of immune cell parameters, mainly of innate immune cells. We attributed an important role to genetic variation in the major histocompatibility complex (MHC) region for these phenotypes and narrowed the signals to probable causal associations in HLA genes. In the third work, forces shaping the gut microbiome composition were investigated. We found a strong influence of several non-genetic factors on overall microbiome diversity and on the abundance of specific bacterial species. We showed as well that genetic factors only play a minor role in gut microbiome composition.

Together, these studies quantified the effects of demographic, environment and genetics on the interindividual variability of phenotypes central to the human immune system. Furthermore, they constitute a valuable resource for further explorations of the impact of immune diversity on the individual risk of infections or of immune diseases.