Molecular mechanisms of phenotypic heterogeneity of chronic obstructive pulmonary disease: the role of JAK / STAT-, NFKB1-signaling pathway and inflammatory response molecules

Chronic obstructive pulmonary disease (COPD) is a multifactorial heterogeneous chronic inflammatory disease of the respiratory system predominantly affecting the lower respiratory pathways and the lung parenchyma. One of the reason for difficulties in identifying of COPD markers is phenotypic heterogeneity. The goal of the study is the identification of new molecular markers of pathogenetic changes associated with phenotypic heterogeneity of COPD based on the analysis of the expression profile of genes involved in the development of the immune response in peripheral blood mononuclear cells and analysis of the association of polymorphic variants of new candidate genes with COPD. Methods: to identify differential gene expression in COPD we performed expression profiling of 84 cytokines and chemokines genes in peripheral blood samples from COPD (N=10 with frequent exacerbation phenotype, N=10 rare exacerbation phenotype) and N=10 smoking controls. RNA was isolated from PBMCs, and gene expression was assessed using RT2 Profiler PCR Arrays «Human Cytokines & Chemokines PCR Array»» (Qiagen, Valencia, CA, USA). 56 SNPs of JAK / STAT-, NFKB1-signaling pathway and inflammatory response molecules genes were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (601 COPD patients and 617 controls). Results. Significant changes were revealed in the expression profile of several genes in “frequent exacerbator» COPD phenotype. The results indicate a down-regulation of inflammatory molecules in “frequent exacerbator» COPD phenotype. For the first time, we indicated the contribution of JAK1, JAK3, STAT3, ICAM1, PECAM1, SAA1, NFKB1, IL17A, CCR2, CCR6, CCL8, CRP, CX3CL1, CXCR2, CXCR1, TNFRSF1A, IL20, IL19 genes polymorphisms to COPD. Specific genetic markers of “frequent exacerbator” COPD phenotype have been identified, which are modifiers of COPD progression, including polymorphic loci of the CXCR2, TNFRSF1B, CCR6, TNF, IL1B, IL10, JAK3, PECAM1 genes. A significant genotype-dependent variation of lung function parameters was observed for CXCR2, JAK1, NFKB1, PECAM1, ICAM1, STAT1, LTA, CD14, CXCL12, CCL20, ADIPOR1 and CX3CR1 genes. The relationship of IL17A, JAK1, JAK3, NFKB1, CCL5, CCL11, CCL17, CXCL8, TNFRSF1A, CX3CL1, CCL8, CCR6, CXCR2, IL19, IL20 genes with smoking pack-years was found.

Chronic Obstructive Pulmonary Disease (COPD), expression profiling