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Nat Commun. 2017 Aug 16;8(1):266. doi: 10.1038/s41467-017-00366-1.

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations.

Author information

1
New York Genome Center, New York, NY, 10013, USA. skim@nygenome.org.
2
Department of Systems Biology, Columbia University, New York, NY, 10032, USA. skim@nygenome.org.
3
Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany. skim@nygenome.org.
4
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany. skim@nygenome.org.
5
Institute of Molecular Medicine, University of Bonn, Bonn, 53127, Germany.
6
Statistical Genetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany.
7
New York Genome Center, New York, NY, 10013, USA.
8
Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
9
Department of Genetics, CHU Sainte-Justine Research Center, Montreal, Canada, H3T 1C5.
10
Department of Biochemistry, University of Montreal, Montreal, Canada, H3C 3J7.
11
Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany.
12
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany.
13
Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, Aachen, 52074, Germany.
14
Department of Pediatrics, University of Montreal, Montreal, Canada, H3T 1C5.
15
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
16
Munich Cluster for Systems Neurology (SyNergy), Munich, 80804, Germany.
17
Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GL, UK.
18
New York Genome Center, New York, NY, 10013, USA. tlappalainen@nygenome.org.
19
Department of Systems Biology, Columbia University, New York, NY, 10032, USA. tlappalainen@nygenome.org.
20
Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany. johannes.schumacher@uni-bonn.de.
21
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany. johannes.schumacher@uni-bonn.de.
22
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität Munich, Munich, 81377, Germany.
23
Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians-Universität Munich, Munich, 81377, Germany.

Abstract

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5'-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

PMID:
28814792
PMCID:
PMC5559603
DOI:
10.1038/s41467-017-00366-1
[Indexed for MEDLINE]
Free PMC Article

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