An integrative genomics approach identifies KDM4 as a modulator of trained immunity

Simone J C F M Moorlag, Vasiliki Matzaraki, Jelmer H van Puffelen Heijden, Charlotte van der Heijden, Sam Keating, Laszlo Groh, Olivier B Bakker, Valerie A C M Koeken, L Charlotte J de Bree, Sanne P Smeekens, Marije Oosting, Raúl Aguirre Gamboa, Niels P Riksen, Ramnik J Xavier, Cisca Wijmenga, Vinod Kumar, Reinout van Crevel, Boris Novakovic, Leo A B Joosten, Yang Li*Mihai G Netea*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Innate immune cells are able to build memory characteristics via a process termed trained immunity. Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.

Original languageEnglish
Pages (from-to)431-446
Number of pages16
JournalEuropean Journal of Immunology
Issue number3
Early online date25-Nov-2021
Publication statusPublished - Mar-2022


  • immunogenomics
  • innate immune memory
  • KDM4
  • QTL mapping
  • trained immunity
  • SIGLEC-14

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