C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis

PLoS Comput Biol. 2017 Sep 18;13(9):e1005766. doi: 10.1371/journal.pcbi.1005766. eCollection 2017 Sep.

Abstract

Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.

MeSH terms

  • Adult
  • C-Reactive Protein / metabolism*
  • CD59 Antigens / blood
  • CD59 Antigens / metabolism*
  • Cohort Studies
  • Estonia
  • Humans
  • Inflammation / metabolism
  • Up-Regulation / physiology

Substances

  • CD59 Antigens
  • CD59 protein, human
  • C-Reactive Protein

Grant support

KL was supported by the European Regional Development Fund (ERDF) through Dora Plus; KL and HP were supported by ERDF for CoE of Estonian ICT research EXCITE and Estonian Research Council grant IUT34-4; KL, HP, PP were supported by Centre of Translational Genomics of University of Tartu (SP1GVARENG). ZK was supported by the Swiss National Science Foundation [31003A_169929] and SystemsX.ch [51RTP0_151019]. This study was also supported by the Estonian Research Agency grants IUT2-2, IUT20-60 and by European Union H2020 grants 692145, Est.RC grant IUT20-60 and EU Project No. 2014-2020.4.01.15-0012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.