Gene-gene and gene-environment interactions of the inflammatory gene variants in the development of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease that is characterized by partly reversible airflow limitation, chronic inflammation, fibrosis of small airways, and destruction of lung parenchyma. We aimed to assess the association of the inflammatory gene loci singly and in combinations with COPD in smokers and non-smokers in ethnic Tatar from Russia to evaluate the gene-gene and gene-environment interactions in COPD development. Eleven loci of inflammatory genes, including IL19, IL20, IL24, PPBP, IL4, IL4RA, С5, FAS, FASLG, and TGFb1, were genotyped in 484 smoking COPD patients, 517 healthy smokers, 117 non-smoking COPD patients, and 100 healthy non-smokers. Significant associations with COPD in smokers were identified for IL19 (rs2243193), IL4 (rs2243250), IL4 (rs2070874), and PPBP (rs352010). In non-smokers, associations were established for IL24 (rs291107), IL4 (rs2070874), and PPBP (rs352010). Associations of inflammatory genes loci IL19 (rs2243193), IL4 (rs2070874), TGFb1 (rs1800469), PPBP (rs352010), and FASLG (rs763110) and smoking index were determined. Associations of FAS (rs1800682), FASLG (rs763110), IL4 (rs2243250), IL4RA (rs1805010), and PPBP (rs352010) loci with pulmonary function variables were observed. The results of gene-gene interactions analysis showed distinctive patterns of association of inflammatory gene loci with COPD in groups stratified by smoking status. The combination of A allele of IL19 (rs2243193), C allele of IL4 (rs2243250), and T allele of PPBP (rs352010) was the main component of the majority of protective gene-gene combination associated with COPD in smokers. The highest risk of COPD was conferred by TT genotype of PPBP (rs352010) in combination with A allele of FAS (rs1800682). While in non-smokers, the most commonly featured was IL24 (rs291107) C allele in protective patterns and IL24 (rs291107) T allele in predisposing combinations. The highest risk of COPD in non-smokers was detected in a gene-gene combination consisting of A allele of IL12RB2 (rs3762317) together with G allele of IL12A (rs2243115), C allele of IL4 (rs2070874), and A allele of IL4RA (rs1805010).