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Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E488-E497. doi: 10.1073/pnas.1714765115. Epub 2017 Dec 27.

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

Author information

1
Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France.
2
Center for Translational Research, Institut Pasteur, 75015 Paris, France.
3
Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, 75015 Paris, France.
4
INSERM U1223, 75015 Paris, France.
5
Department of Cancer Immunology, Genentech Inc., San Francisco, CA 94080.
6
CNRS Unité de Recherche Associée 3012, 75015 Paris, France.
7
Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France.
8
Department of Automatic Control, Lund University, Lund SE-221, Sweden.
9
International Group for Data Analysis, Institut Pasteur, 75015 Paris, France.
10
Translational Research Department, Genomic Platform, Institut Curie, Paris Sciences et Lettres Research University, 75248 Paris, France.
11
School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
12
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
13
Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; quintana@pasteur.fr.

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.

KEYWORDS:

age; gene expression; genetics; human immune variation; sex

PMID:
29282317
PMCID:
PMC5776984
DOI:
10.1073/pnas.1714765115
[Indexed for MEDLINE]
Free PMC Article

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