An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility

PLoS One. 2017 Jul 20;12(7):e0180824. doi: 10.1371/journal.pone.0180824. eCollection 2017.

Abstract

Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets.

MeSH terms

  • Candidemia / genetics*
  • Female
  • Gene Expression Profiling
  • Genetic Predisposition to Disease*
  • Genotype*
  • Humans
  • Male
  • Sequence Analysis, RNA
  • Transcriptome*

Grant support

This work was supported by an ERC Consolidator Grant [FP/2007-2013/ERC grant 2012-310372 to M.G.N.], an ERC Advanced grant [FP/2007-2013/ERC grant 2012-322698 to C.W.], a Spinoza prize grant [NWO SPI 92-266 to C.W.], a European Union Seventh Framework Programme grant (EU FP7) TANDEM project [HEALTH-F3-2012-305279 to C.W. and V.K.] and an NWO VENI grant [863.13.011 to Y.L.]. V.M. is supported by a PhD scholarship from Graduate School of Medical Sciences, University of Groningen, the Netherlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.