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

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-1 beta, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1 alpha (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 x 10(-20)), at 17q21.32 (p = 1.51 x 10(-9)) and at 10p12.1 (p = 2.76 x 10(-9)) for IL-1 beta, at 10p13 for MIP-1 alpha (CCL3) (p = 2.28 x 10(-9)), and at 9q34.12 for IL-10 (p = 4.52 x 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.