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

TitleGenetic regulatory effects modified by immune activation contribute to autoimmune disease associations.
Publication TypeJournal Article
Year of Publication2017
AuthorsKim-Hellmuth, S, Bechheim, M, Pütz, B, Mohammadi, P, Nédélec, Y, Giangreco, N, Becker, J, Kaiser, V, Fricker, N, Beier, E, Boor, P, Castel, SE, Nöthen, MM, Barreiro, LB, Pickrell, JK, Müller-Myhsok, B, Lappalainen, T, Schumacher, J, Hornung, V
JournalNat Commun
Date Published2017 08 16
KeywordsAcetylmuramyl-Alanyl-Isoglutamine, Adjuvants, Immunologic, Adolescent, Adult, Autoimmune Diseases, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Healthy Volunteers, Humans, Indicators and Reagents, Lipids, Lipopolysaccharides, Male, Monocytes, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, RNA, Double-Stranded, RNA, Messenger, Young Adult

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.

Alternate JournalNat Commun
PubMed ID28814792
PubMed Central IDPMC5559603
Grant ListHHSN268201000009C / HL / NHLBI NIH HHS / United States
R01 MH106842 / MH / NIMH NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
U24 DK112331 / DK / NIDDK NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN268201000002C / HL / NHLBI NIH HHS / United States
/ / European Research Council / International