Genetic dissection of host immune response in pneumonia development and progression.

Tamara V Smelaya,Olesya B Belopolskaya,Lyubov E Salnikova,Svetlana V Smirnova,Artem N Kuzovlev,Viktor V Moroz,Noel A Pabalan,Arkadiy M Golubev

doi:10.1038/srep35021

Abstract

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.

Highlights

Variations being performed for the genes of TNFa4, MBL25, IL66,7, IL107, and FCGR2A6 with no association effect and for the loci ACE8 and TLR49 found to be associated with pneumonia
Several studies showed that genetic associations of sepsis in pneumonia differ from those in other infections[10,11,12] and may in particular depend on a specific pathogen[13]
SNP frequencies were in Hardy– Weinberg equilibrium (HWE) in both control groups with an exception for TLR4 rs4986791 (CAP controls)

Summary

Introduction

Variations being performed for the genes of TNFa4, MBL25, IL66,7, IL107, and FCGR2A6 with no association effect and for the loci ACE8 and TLR49 found to be associated with pneumonia. Several studies showed that genetic associations of sepsis in pneumonia differ from those in other infections[10,11,12] and may in particular depend on a specific pathogen[13]. Taking into account this scientific background the aim of our study was: (i) to investigate the role of the SNPs in the genes of proinflammatory cytokines (IL6, IL1B, IL8), antiinflammatory cytokines (IL10, IL4, IL13) and toll-like receptors TLR2, TLR4 and TLR9 in CAP and HAP patients, (ii) to combine existent knowledge and our own experimental data on the above genes in a series of meta-analyses of genetic susceptibility to pneumonia development and outcome. With the use of database information, we explored linkage disequilibrium structure along with functional annotations of the SNPs within the genes under study

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Conclusion