000261369 001__ 261369
000261369 005__ 20190509131804.0
000261369 0247_ $$2doi$$a10.5075/epfl-thesis-8955
000261369 037__ $$aTHESIS
000261369 041__ $$aeng
000261369 088__ $$a8955
000261369 245__ $$aGenetic determinants of healthy human immune variance: from humoral response to microbiome diversity
000261369 260__ $$c2018$$bEPFL$$aLausanne
000261369 269__ $$a2018
000261369 300__ $$a114
000261369 336__ $$aTheses
000261369 502__ $$aProf. Bruno Emanuel Ferreira De Sousa Correia (président) ; Prof. Jacques Fellay, Prof. Bart Deplancke (directeurs) ; Prof. Felix Naef, Prof. David Gfeller, Prof. Antonio Rausell (rapporteurs)
000261369 520__ $$aIdentifying 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.
000261369 592__ $$b2018
000261369 6531_ $$aImmunity
000261369 6531_ $$aInfection
000261369 6531_ $$aVaccination
000261369 6531_ $$aGWAS
000261369 6531_ $$aSerology
000261369 6531_ $$aHuman genomics
000261369 6531_ $$aImmunoglobulins
000261369 6531_ $$aMicrobiome
000261369 6531_ $$aDemographics
000261369 6531_ $$aEnvironment.
000261369 700__ $$0248556$$aScepanovic, Petar$$g248019
000261369 720_2 $$aFellay, Jacques$$edir.$$g213497
000261369 720_2 $$aDeplancke, Bart$$edir.$$g182376
000261369 8564_ $$uhttps://infoscience.epfl.ch/record/261369/files/EPFL_TH8955.pdf$$s9694359
000261369 909C0 $$pGR-FE
000261369 909CO $$pSV$$pDOI$$ooai:infoscience.epfl.ch:261369$$pthesis
000261369 918__ $$aSV$$cGHI$$dEDBB
000261369 919__ $$aGR-FE
000261369 920__ $$a2018-12-14$$b2018
000261369 970__ $$a8955/THESES
000261369 973__ $$sPUBLISHED$$aEPFL
000261369 980__ $$aTHESIS