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.
Highlights
The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital
An increasingly popular approach to identifying genetic factors influencing the interindividual variation in immune response is to map expression quantitative trait loci —variants that associate with gene expression—and to identify so-called response eQTLs where the eQTL effect differs between immune stimuli
For the full eQTL cohort, we analyzed primary monocytes isolated from 134 healthy male individuals (185 before quality control), which were either left untreated or stimulated with the same three pathogen-derived stimuli, and gene expression was profiled after 90 min and 6 h
Summary
The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. 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. An increasingly popular approach to identifying genetic factors influencing the interindividual variation in immune response is to map expression quantitative trait loci (eQTLs) —variants that associate with gene expression—and to identify so-called response eQTLs (reQTLs) where the eQTL effect differs between immune stimuli. Such genetic variants can impact the transcriptional response to infection, and represent genetic effects that are modified by the infectious environment via gene-by-environment interactions. We provide a user-friendly access to our results via the ImmunPop QTL browser (http://immunpop.com/kim/eQTL)
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