Advanced

Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges

Piasecka, Barbara ; Duffy, Darragh ; Urrutia, Alejandra ; Quach, Helene ; Patin, Etienne ; Posseme, Céline ; Bergstedt, Jacob LU ; Charbit, Bruno ; Rouilly, Vincent and MacPherson, Cameron R. , et al. (2017) In Proceedings of the National Academy of Sciences 115(3). p.488-497
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
115
issue
3
pages
8 pages
publisher
National Acad Sciences
external identifiers
  • scopus:85042117261
ISSN
1091-6490
project
ELLIIT-sched
LCCC
language
English
LU publication?
yes
id
ba5e0f8a-1225-4813-ac96-1a3d7150b367
alternative location
http://www.pnas.org/content/115/3/E488.full
date added to LUP
2018-01-02 08:54:28
date last changed
2020-10-07 05:39:38
@article{ba5e0f8a-1225-4813-ac96-1a3d7150b367,
  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.},
  author       = {Piasecka, Barbara and Duffy, Darragh and Urrutia, Alejandra and Quach, Helene and Patin, Etienne and Posseme, Céline and Bergstedt, Jacob and Charbit, Bruno and Rouilly, Vincent and MacPherson, Cameron R. and Hasan, Milena and Albaud, Benoit and Gentien, David and Fellay, Jacques and Albert, Matthew L. and Quintana-Murci, Lluis},
  issn         = {1091-6490},
  language     = {eng},
  month        = {12},
  number       = {3},
  pages        = {488--497},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges},
  url          = {http://www.pnas.org/content/115/3/E488.full},
  volume       = {115},
  year         = {2017},
}