Dataset Information

Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia.

ABSTRACT:

Background

Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient's heterogeneity.

Methods

For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants.

Results

102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10^-20), at 17q21.32 (p = 1.51 × 10^-9) and at 10p12.1 (p = 2.76 × 10^-9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10^-9), and at 9q34.12 for IL-10 (p = 4.52 × 10^-8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics.

Conclusion

This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms.

SUBMITTER: Kuhnapfel A

PROVIDER: S-EPMC8774373 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCommunity-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP.MethodsWe measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls. We stratified the biomarkers into several pathophysiological domains- antiviral response, vascular response and function, coagulation, systemic inflammation, and immune checkpoint markers. We directly compared CAP caused by SARS-CoV-2 (COVID-19, n=39), Streptococcus pneumoniae (CAP-strep, n=27), Influenza (CAP-flu, n=22) and other or unknown pathogens (CAP-other, n=177). We adjusted the comparisons for age, sex and disease severity scores.FindingsBiomarkers reflective of a stronger cell-mediated antiviral response clearly separated COVID-19 from other CAPs (most notably granzyme B). Biomarkers reflecting activation and function of the vasculature showed endothelial barrier integrity was least affected in COVID-19, while glycocalyx degradation and angiogenesis were enhanced relative to other CAPs. Notably, markers of coagulation activation, including D-dimer, were not different between the CAP groups. Ferritin was most increased in COVID-19, while other systemic inflammation biomarkers such as IL-6 and procalcitonin were highest in CAP-strep. Immune checkpoint markers showed distinctive patterns in viral and non-viral CAP, with highly elevated levels of Galectin-9 in COVID-19.InterpretationOur investigation provides insight into shared and distinct pathophysiological mechanisms in different aetiologies of CAP, which may help guide new pathogen-specific therapeutic strategies.FundingThis study was financially supported by the Dutch Research Council, the European Commission and the Netherlands Organization for Health Research and Development.