1. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges
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Barbara, Piasecka, Darragh, Duffy, Alejandra, Urrutia, Hélène, Quach, Etienne, Patin, Céline, Posseme, Jacob, Bergstedt, Bruno, Charbit, Vincent, Rouilly, Cameron R, MacPherson, Milena, Hasan, Benoit, Albaud, David, Gentien, Jacques, Fellay, Matthew L, Albert, Lluis, Quintana-Murci, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc., Genentech, Inc. [San Francisco], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), This work was supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01., We acknowledge Stephanie Thomas for managing the Milieu Intérieur Consortium. Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre de Recherche Translationnelle ( CRT ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Bioinformatique, Biostatistique et Biologie Intégrative ( C3BI ), International Group for Data Analysis ( IGDA ), Institut Curie, Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Milieu Intérieur Consortium, Abel, L., Alcover, A., Aschard, H., Aström, K., Bousso, P., Bruhns, P., Cumano, A., Duffy, D., Demangel, C., Deriano, L., Di Santo, J., Dromer, F., Eberl, G., Enninga, J., Fellay, J., Fontes, M., Freitas, A., Gelpi, O., Gomperts-Boneca, I., Hercberg, S., Lantz, O., Leclerc, C., Mouquet, H., Patin, E., Pellegrini, S., Pol, S., Raussel, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Soumelis, V., Tangy, F., Tartour, E., Toubert, A., Ungeheuer, M.N., Quintana-Murci, L., and Albert, M.L.
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Adult ,Male ,Aging ,Genotype ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Quantitative Trait Loci ,[ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology ,Cohort Studies ,Enterotoxins ,Young Adult ,Immunology and Inflammation ,Humans ,sex ,genetics ,[ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics ,Aged ,[ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity ,Bacteria ,Fungi ,Genetic Variation ,Middle Aged ,Biological Sciences ,Bacteria/immunology ,Enterotoxins/immunology ,Female ,Fungi/immunology ,Gene Expression Regulation/immunology ,Influenza A virus/immunology ,age ,gene expression ,human immune variation ,[ SDV.GEN.GPO ] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE] ,[ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Gene Expression Regulation ,PNAS Plus ,Influenza A virus ,[SDV.IMM]Life Sciences [q-bio]/Immunology - Abstract
Significance Identifying the drivers of the interindividual diversity of the human immune system is crucial to understand their consequences on immune-mediated diseases. By examining the transcriptional responses of 1,000 individuals to various microbial challenges, we show that age and sex influence the expression of many immune-related genes, but their effects are overall moderate, whereas genetic factors affect a smaller gene set but with a stronger effect. We identify numerous genetic variants that affect transcriptional variation on infection, many of which are associated with autoimmune or inflammatory disorders. These results enable additional exploration of the role of regulatory variants in the pathogenesis of immune-related diseases and improve our understanding of the respective effects of age, sex, and genetics on immune response variation., The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
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- 2018
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