Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
Identifieur interne : 000290 ( PubMed/Corpus ); précédent : 000289; suivant : 000291Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
Auteurs : 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-MurciSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.
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
Links to Exploration step
pubmed:29282317Le document en format XML
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Albert</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></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><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; quintana@pasteur.fr.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29282317</idno><idno type="pmid">29282317</idno><idno type="doi">10.1073/pnas.1714765115</idno><idno type="wicri:Area/PubMed/Corpus">000290</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000290</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.</title><author><name sortKey="Piasecka, Barbara" sort="Piasecka, Barbara" uniqKey="Piasecka B" first="Barbara" last="Piasecka">Barbara Piasecka</name><affiliation><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Duffy, Darragh" sort="Duffy, Darragh" uniqKey="Duffy D" first="Darragh" last="Duffy">Darragh Duffy</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Urrutia, Alejandra" sort="Urrutia, Alejandra" uniqKey="Urrutia A" first="Alejandra" last="Urrutia">Alejandra Urrutia</name><affiliation><nlm:affiliation>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Quach, Helene" sort="Quach, Helene" uniqKey="Quach H" first="Hélène" last="Quach">Hélène Quach</name><affiliation><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Patin, Etienne" sort="Patin, Etienne" uniqKey="Patin E" first="Etienne" last="Patin">Etienne Patin</name><affiliation><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Posseme, Celine" sort="Posseme, Celine" uniqKey="Posseme C" first="Céline" last="Posseme">Céline Posseme</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Bergstedt, Jacob" sort="Bergstedt, Jacob" uniqKey="Bergstedt J" first="Jacob" last="Bergstedt">Jacob Bergstedt</name><affiliation><nlm:affiliation>Department of Automatic Control, Lund University, Lund SE-221, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Charbit, Bruno" sort="Charbit, Bruno" uniqKey="Charbit B" first="Bruno" last="Charbit">Bruno Charbit</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Rouilly, Vincent" sort="Rouilly, Vincent" uniqKey="Rouilly V" first="Vincent" last="Rouilly">Vincent Rouilly</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></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><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Hasan, Milena" sort="Hasan, Milena" uniqKey="Hasan M" first="Milena" last="Hasan">Milena Hasan</name><affiliation><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Albaud, Benoit" sort="Albaud, Benoit" uniqKey="Albaud B" first="Benoit" last="Albaud">Benoit Albaud</name><affiliation><nlm:affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Gentien, David" sort="Gentien, David" uniqKey="Gentien D" first="David" last="Gentien">David Gentien</name><affiliation><nlm:affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fellay, Jacques" sort="Fellay, Jacques" uniqKey="Fellay J" first="Jacques" last="Fellay">Jacques Fellay</name><affiliation><nlm:affiliation>School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.</nlm:affiliation></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><nlm:affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</nlm:affiliation></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><nlm:affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; quintana@pasteur.fr.</nlm:affiliation></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="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Enterotoxins</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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29282317</PMID><DateCompleted><Year>2018</Year><Month>07</Month><Day>17</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN><JournalIssue CitedMedium="Internet"><Volume>115</Volume><Issue>3</Issue><PubDate><Year>2018</Year><Month>01</Month><Day>16</Day></PubDate></JournalIssue><Title>Proceedings of the National Academy of Sciences of the United States of America</Title><ISOAbbreviation>Proc. Natl. Acad. Sci. U.S.A.</ISOAbbreviation></Journal><ArticleTitle>Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.</ArticleTitle><Pagination><MedlinePgn>E488-E497</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1714765115</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2018 the Author(s). Published by PNAS.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Piasecka</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Duffy</LastName><ForeName>Darragh</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>INSERM U1223, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Urrutia</LastName><ForeName>Alejandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>INSERM U1223, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Cancer Immunology, Genentech Inc., San Francisco, CA 94080.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Quach</LastName><ForeName>Hélène</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>CNRS Unité de Recherche Associée 3012, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Patin</LastName><ForeName>Etienne</ForeName><Initials>E</Initials><Identifier Source="ORCID">0000-0002-9911-4459</Identifier><AffiliationInfo><Affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>CNRS Unité de Recherche Associée 3012, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Posseme</LastName><ForeName>Céline</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bergstedt</LastName><ForeName>Jacob</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Automatic Control, Lund University, Lund SE-221, Sweden.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>International Group for Data Analysis, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Charbit</LastName><ForeName>Bruno</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rouilly</LastName><ForeName>Vincent</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>MacPherson</LastName><ForeName>Cameron R</ForeName><Initials>CR</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hasan</LastName><ForeName>Milena</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Albaud</LastName><ForeName>Benoit</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gentien</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fellay</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0002-8240-939X</Identifier><AffiliationInfo><Affiliation>School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Albert</LastName><ForeName>Matthew L</ForeName><Initials>ML</Initials><AffiliationInfo><Affiliation>Center for Translational Research, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>INSERM U1223, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Cancer Immunology, Genentech Inc., San Francisco, CA 94080.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Quintana-Murci</LastName><ForeName>Lluis</ForeName><Initials>L</Initials><Identifier Source="ORCID">0000-0003-2429-6320</Identifier><AffiliationInfo><Affiliation>Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; quintana@pasteur.fr.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>CNRS Unité de Recherche Associée 3012, 75015 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>Milieu Intérieur Consortium</CollectiveName></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>12</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Proc Natl Acad Sci U S A</MedlineTA><NlmUniqueID>7505876</NlmUniqueID><ISSNLinking>0027-8424</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004768">Enterotoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>39424-53-8</RegistryNumber><NameOfSubstance UI="C031818">enterotoxin B, staphylococcal</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000375" MajorTopicYN="Y">Aging</DescriptorName></MeshHeading><MeshHeading><DescriptorName 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