Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
Identifieur interne : 000A09 ( Main/Exploration ); précédent : 000A08; suivant : 000A10Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
Auteurs : Barbara Piasecka [France] ; Darragh Duffy [France] ; Alejandra Urrutia [France] ; Hélène Quach [France] ; Etienne Patin [France] ; Céline Posseme [France] ; Jacob Bergstedt [Suède] ; Bruno Charbit [France] ; Vincent Rouilly [France] ; Cameron R. Macpherson [France] ; Milena Hasan [France] ; Benoit Albaud [France] ; David Gentien [France] ; Jacques Fellay [Suisse] ; Matthew L. Albert [France] ; Lluis Quintana-Murci [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.
Descripteurs français
- KwdFr :
- Adulte, Adulte d'âge moyen, Bactéries (immunologie), Champignons (immunologie), Entérotoxines (immunologie), Femelle, Génotype, Humains, Jeune adulte, Locus de caractère quantitatif, Mâle, Régulation de l'expression des gènes (immunologie), Sujet âgé, Variation génétique, Vieillissement, Virus de la grippe A (immunologie), Études de cohortes.
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , immunology : Enterotoxins.
- immunology : Bacteria, Fungi, Gene Expression Regulation, Influenza A virus.
- Adult, Aged, Aging, Cohort Studies, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Quantitative Trait Loci, Young Adult.
Abstract
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.
DOI: 10.1073/pnas.1714765115
PubMed: 29282317
Affiliations:
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sort="Quach, Helene" uniqKey="Quach H" first="Hélène" last="Quach">Hélène Quach</name><affiliation wicri:level="3"><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Patin, Etienne" sort="Patin, Etienne" uniqKey="Patin E" first="Etienne" last="Patin">Etienne Patin</name><affiliation wicri:level="3"><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement 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wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Urrutia, Alejandra" sort="Urrutia, Alejandra" uniqKey="Urrutia A" first="Alejandra" last="Urrutia">Alejandra Urrutia</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Quach, Helene" sort="Quach, Helene" uniqKey="Quach H" first="Hélène" last="Quach">Hélène Quach</name><affiliation wicri:level="3"><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Patin, Etienne" sort="Patin, Etienne" uniqKey="Patin E" first="Etienne" last="Patin">Etienne Patin</name><affiliation wicri:level="3"><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Posseme, Celine" sort="Posseme, Celine" uniqKey="Posseme C" first="Céline" last="Posseme">Céline Posseme</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Bergstedt, Jacob" sort="Bergstedt, Jacob" uniqKey="Bergstedt J" first="Jacob" last="Bergstedt">Jacob Bergstedt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Automatic Control, Lund University, Lund SE-221, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Automatic Control, Lund University, Lund SE-221</wicri:regionArea><wicri:noRegion>Lund SE-221</wicri:noRegion></affiliation></author><author><name sortKey="Charbit, Bruno" sort="Charbit, Bruno" uniqKey="Charbit B" first="Bruno" last="Charbit">Bruno Charbit</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Rouilly, Vincent" sort="Rouilly, Vincent" uniqKey="Rouilly V" first="Vincent" last="Rouilly">Vincent Rouilly</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Macpherson, Cameron R" sort="Macpherson, Cameron R" uniqKey="Macpherson C" first="Cameron R" last="Macpherson">Cameron R. Macpherson</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Hasan, Milena" sort="Hasan, Milena" uniqKey="Hasan M" first="Milena" last="Hasan">Milena Hasan</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Albaud, Benoit" sort="Albaud, Benoit" uniqKey="Albaud B" first="Benoit" last="Albaud">Benoit Albaud</name><affiliation wicri:level="3"><nlm:affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Gentien, David" sort="Gentien, David" uniqKey="Gentien D" first="David" last="Gentien">David Gentien</name><affiliation wicri:level="3"><nlm:affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Fellay, Jacques" sort="Fellay, Jacques" uniqKey="Fellay J" first="Jacques" last="Fellay">Jacques Fellay</name><affiliation wicri:level="1"><nlm:affiliation>School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Albert, Matthew L" sort="Albert, Matthew L" uniqKey="Albert M" first="Matthew L" last="Albert">Matthew L. Albert</name><affiliation wicri:level="3"><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Center for Translational Research, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Quintana Murci, Lluis" sort="Quintana Murci, Lluis" uniqKey="Quintana Murci L" first="Lluis" last="Quintana-Murci">Lluis Quintana-Murci</name><affiliation wicri:level="3"><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; quintana@pasteur.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aging</term><term>Bacteria (immunology)</term><term>Cohort Studies</term><term>Enterotoxins (immunology)</term><term>Female</term><term>Fungi (immunology)</term><term>Gene Expression Regulation (immunology)</term><term>Genetic Variation</term><term>Genotype</term><term>Humans</term><term>Influenza A virus (immunology)</term><term>Male</term><term>Middle Aged</term><term>Quantitative Trait Loci</term><term>Young Adult</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Bactéries (immunologie)</term><term>Champignons (immunologie)</term><term>Entérotoxines (immunologie)</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Jeune adulte</term><term>Locus de caractère quantitatif</term><term>Mâle</term><term>Régulation de l'expression des gènes (immunologie)</term><term>Sujet âgé</term><term>Variation génétique</term><term>Vieillissement</term><term>Virus de la grippe A (immunologie)</term><term>Études de cohortes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Enterotoxins</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Bactéries</term><term>Champignons</term><term>Entérotoxines</term><term>Régulation de l'expression des gènes</term><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Bacteria</term><term>Fungi</term><term>Gene Expression Regulation</term><term>Influenza A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aging</term><term>Cohort Studies</term><term>Female</term><term>Genetic Variation</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Quantitative Trait Loci</term><term>Young Adult</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Jeune adulte</term><term>Locus de caractère quantitatif</term><term>Mâle</term><term>Sujet âgé</term><term>Variation génétique</term><term>Vieillissement</term><term>Études de cohortes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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<sup>+</sup> T cells for age and CD4<sup>+</sup> 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 <i>Candida albicans</i>-specific master regulator at the <i>CR1</i> 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.</div></front></TEI><affiliations><list><country><li>France</li><li>Suisse</li><li>Suède</li></country><region><li>Canton de Vaud</li><li>Île-de-France</li></region><settlement><li>Lausanne</li><li>Paris</li></settlement></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Piasecka, Barbara" sort="Piasecka, Barbara" uniqKey="Piasecka B" first="Barbara" last="Piasecka">Barbara Piasecka</name></region><name sortKey="Albaud, Benoit" sort="Albaud, Benoit" uniqKey="Albaud B" first="Benoit" last="Albaud">Benoit Albaud</name><name sortKey="Albert, Matthew L" sort="Albert, Matthew L" uniqKey="Albert M" first="Matthew L" last="Albert">Matthew L. Albert</name><name sortKey="Charbit, Bruno" sort="Charbit, Bruno" uniqKey="Charbit B" first="Bruno" last="Charbit">Bruno Charbit</name><name sortKey="Duffy, Darragh" sort="Duffy, Darragh" uniqKey="Duffy D" first="Darragh" last="Duffy">Darragh Duffy</name><name sortKey="Gentien, David" sort="Gentien, David" uniqKey="Gentien D" first="David" last="Gentien">David Gentien</name><name sortKey="Hasan, Milena" sort="Hasan, Milena" uniqKey="Hasan M" first="Milena" last="Hasan">Milena Hasan</name><name sortKey="Macpherson, Cameron R" sort="Macpherson, Cameron R" uniqKey="Macpherson C" first="Cameron R" last="Macpherson">Cameron R. Macpherson</name><name sortKey="Patin, Etienne" sort="Patin, Etienne" uniqKey="Patin E" first="Etienne" last="Patin">Etienne Patin</name><name sortKey="Posseme, Celine" sort="Posseme, Celine" uniqKey="Posseme C" first="Céline" last="Posseme">Céline Posseme</name><name sortKey="Quach, Helene" sort="Quach, Helene" uniqKey="Quach H" first="Hélène" last="Quach">Hélène Quach</name><name sortKey="Quintana Murci, Lluis" sort="Quintana Murci, Lluis" uniqKey="Quintana Murci L" first="Lluis" last="Quintana-Murci">Lluis Quintana-Murci</name><name sortKey="Rouilly, Vincent" sort="Rouilly, Vincent" uniqKey="Rouilly V" first="Vincent" last="Rouilly">Vincent Rouilly</name><name sortKey="Urrutia, Alejandra" sort="Urrutia, Alejandra" uniqKey="Urrutia A" first="Alejandra" last="Urrutia">Alejandra Urrutia</name></country><country name="Suède"><noRegion><name sortKey="Bergstedt, Jacob" sort="Bergstedt, Jacob" uniqKey="Bergstedt J" first="Jacob" last="Bergstedt">Jacob Bergstedt</name></noRegion></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Fellay, Jacques" sort="Fellay, Jacques" uniqKey="Fellay J" first="Jacques" last="Fellay">Jacques Fellay</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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