The role of host genetic variation in pneumonia development and outcome is poorly understood. We studied common polymorphisms in the genes of proinflammatory cytokines (IL6 rs1800795, IL8 rs4073, IL1B rs16944), anti-inflammatory cytokines (IL10 rs1800896, IL4 rs2243250, IL13 rs20541) and toll-like receptors (TLR2 rs5743708 and rs4696480, TLR4 rs4986791, TLR9 rs352139, rs5743836 and rs187084) in patients with community-acquired pneumonia (CAP) (390 cases, 203 controls) and nosocomial pneumonia (355 cases, 216 controls). Experimental data were included in a series of 11 meta-analyses and eight subset analyses related to pneumonia susceptibility and outcome. TLR2 rs5743708 minor genotype appeared to be associated with CAP/Legionnaires' disease/pneumococcal disease. In CAP patients, the IL6 rs1800795-C allele was associated with severe sepsis/septic shock/severe systemic inflammatory response, while the IL10 rs1800896-A allele protected against the development of these critical conditions. To contribute to deciphering of the above results, we performed an in silico analysis and a qualitative synthesis of literature data addressing basal and stimulated genotype-specific expression level. This data together with database information on transcription factors' affinity changes caused by SNPs in putative promoter regions, the results of linkage disequilibrium analysis along with SNPs functional annotations supported assumptions about the complexity underlying the revealed associations. Pneumonia, one of the most common infectious diseases, is associated with high morbidity and mortality worldwide. Pneumonia is classified according to the site of acquisition as community-acquired (CAP) and hospital-acquired (or nosocomial) pneumonia (HAP or NP), which includes healthcare-associated pneumonia (HCAP) and ventilator-associated pneumonia (VAP). HAP tends to be a more serious problem than CAP since HAP patients have an increased risk of infection caused by antibiotic-resistant organisms, besides they are often older and burdened by comorbidities. Pneumonia is considered to be the the most prevalent cause of sepsis associated with the highest mortality rates 1 . In infection, host genetic background may be of even more importance than in cancer and cardiovascular diseases which are known to have a high hereditary component 2 . Most infectious phenotypes result from a complex interplay between multiple genetic factors related to host and pathogen genetics and a variety of non-genetic factors. Since infectious diseases are related to immune-mediated disorders, genetic susceptibility loci for immune traits can be considered as good candidates in genetic association studies of pneumonia and its complications 3 . The first line of defence of the innate immune system is represented by pattern-recognition receptors that sense bacterial, viral or fungal molecular structures and induce systemic inflammation. The most studied class of pattern-recognition receptors is that of the toll-like receptors (TLRs). Once inflammation has been launched a crosstalk between pro-and anti-inflammatory branches of the immune response should provide a balanced immune reaction crucial for a favorable resolution of infection. Genetic studies of pneumonia are not numerous while investigations assessing the role of host genetics in sepsis due to pneumonia are even more unfrequent. Furthermore, to date there are no GWAS reported for pneumonia. Meta-analyses of genetic susceptibility to pneumonia provided very limited coverage of common genetic 1 V. A. Negovsky Research Institute of General Reanimatology, Russian Academy of Sciences, 25 Petrovka str., build.2,
Output: Genetic dissection of host immune response in pneumonia development and progression OPEN