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.
Highlights
Increased levels of C-reactive protein (CRP) in the blood are associated with tissue injury, infections and inflammation [1]
We studied the functional role of C-reactive protein (CRP)–an inflammatory biomarker that is used to measure cardiovascular risk in clinical practice
There is evidence for a strong genetic component of elevated CRP levels but it is still unclear if it has a direct impact on the processes that lead to inflammatory diseases
Summary
Increased levels of C-reactive protein (CRP) in the blood are associated with tissue injury, infections and inflammation [1]. In addition to acute bacterial and viral infections, chronically elevated CRP levels are predictive of multiple diseases associated with inflammatory processes, e.g. cardiovascular disease (CVD). Genome-wide association studies (GWAS) have identified thousands of disease-associated genetic loci, and a GWAS meta-analysis of CRP levels in over 80,000 individuals found a number of allelic variants in genes implicated in pathways related to metabolism and immune system [6]. These studies have demonstrated a strong genetic component in chronic inflammatory processes. Causal inference methods and multi-omics approaches have already been applied successfully in the analysis of complex traits, e.g. obesity, cancer and coronary artery disease [7,8,9,10]
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