  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-1b, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1a
(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=1.58x10E-20), at 17q21.32 (p=1.51x10E-9) and at 10p12.1 (p=2.76x10E-9) for
IL-1b, at 10p13 for MIP-1a (CCL3) (p=2.28x10E-9), and at 9q34.12 for IL-10
(p=4.52x10E-8). Functionally plausible genes could be assigned to the majority
of loci including genes involved in cytokine secretion, granulocyte function,
and cilial kinetics. Conclusions: 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.
