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Global Translational Medicine Inflammatory gene-environment interactions in COPD

1. Introduction IL24, PPBP, IL4, IL4RA, С5, FAS, FASLG, and TGFb1
genes singly and in combinations with COPD in smokers
Chronic obstructive pulmonary disease (COPD) is a and non-smokers to evaluate the gene-gene and gene-
complex lung disease characterized by progressive airflow environment interactions in COPD development.
limitation and abnormal inflammatory response of the
lungs to the inhaled noxious particles [1,2] . COPD is one 2. Materials and methods
of the most common chronic respiratory diseases with
[3]
high morbidity and mortality rates . Tobacco smoking, 2.1. Study population
environmental pollution, and genetic predisposition are the All participants of this study provided written informed
principal risk factors of COPD with genetic contributions consent and the study was approved by the Local Research
from multiple genes [4,5] . COPD pathogenesis was linked Ethics Committee (Ufa, Protocol No 17, December 07,
to oxidative stress and systemic inflammation . To date, 2010). We included unrelated subjects of self-reported
[6]
comprehensive studies of COPD genetic background are ethnic Tatar population; all details have been previously
being conducted . There is evidence that the genes of described [26,27] . The participants were recruited through
[7]
cytokines and inflammatory mediators play an important the pulmonary departments of Ufa City Hospitals No. 21
roles in the development of COPD [8-10] . (Ufa, Russia) during the 2010 – 2020 period. The smoker
group includes 484 COPD patients and 517 healthy
Cytokines are secreted proteins with key functions that
regulate immune responses [11,12] . IL19, IL20, and IL24 are individuals, while the non-smoker group includes 117
COPD patients and 100 healthy individuals. Details of
proinflammatory cytokines of the IL20 subfamily members inclusion and exclusion criteria for case and control groups
within the IL10 cytokine family, which can bind the IL20 have been previously described [24,26] . Briefly, to determine
receptor complex IL-20R1/IL-20R2 [13-15] . IL4 is cytokine pulmonary function, measures of forced expiratory
produced by activated T cells and binds to the IL4 receptor. volume in 1 second (FEV ) and forced vital capacity (FVC)
As an important cytokine for tissue repair, IL4 also were derived in accordance with American Thoracic
1
promotes allergic airway inflammation, as well as mediates Society/European Respiratory Society criteria . COPD
[28]
and regulates a variety of human host responses . was diagnosed according to the Tenth Revision of the
[16]
Chemokines play a key role to the formation of immune International Classification of Diseases (ICD 10) (http://
responses . Pro-platelet basic protein (PPBP) is a platelet- www.who.int/classifications/icd/en/) and in accordance
[17]
derived growth factor or platelet-derived chemokine with the recommendations of the Global Initiative on
ligand 7 chemokine (CXCL7), which is a member of the COPD (GOLD; http www.goldcopd.org) [26,27] . Baseline
CXC-chemokine family . This growth factor is a potent demographics and clinical characteristics of studied groups
[18]
chemoattractant and activator of neutrophils . CXCL are presented in Table 1.
[19]
chemokines are produced by inflammatory cells and
endothelial cells, and CXCL7 displays chemotactic activity 2.2. Gene and SNPs selection and genotyping
on neutrophils. The receptors CXCR1 and CXCR2 for Eleven SNPs of inflammatory genes (Table 2), including
CXCL7 are expressed on neutrophils, endothelial cells, and FASLG (rs763110), IL19 (rs2243193), IL20 (rs2981573),
[20]
macrophages . IL24 (rs291107), PPBP (rs352010), IL4 (rs2243250),
IL4 (rs2070874), С5 (rs17611), FAS (rs1800682), IL4RA
The FASL/FAS system is considered a major pathway
for apoptosis in cells and tissues. FAS plays a central (rs1805010), and TGFb1 (rs1800469), were selected for the
[26,27]
role in the physiological regulation of programmed cell study based on the following criteria : (i) Associations
death , as well as in pulmonary inflammation, injury, and with complex human diseases; (ii) functional effect of
[21]
fibrosis . The transforming growth factor beta (TGF-β) SNP on gene expression or relation to non-synonymous
[22]
superfamily consists of secreted growth factors involved substitutions; and (iii) minor allele frequency (MAF)
in the regulation of different cellular processes . TGF-β1 of ≥5% in the European populations (http://www.
[23]
internationalgenome.org/). The SNPs regulatory potential
plays a key role in tissue injury and airway remodeling in and effect on the gene expression were assessed using
smokers . C5 (complement C5) is a component of the HaploReg (v 4.1; http://archive.broadinstitute.org/
[24]
complement system, which is a part of the innate immune mammals/haploreg/haploreg.php) , SNPinfo Web
[29]
system .
[25]
Server (https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.
Previously, we identified the association of chemokines html), RegulomeDB Version 1.1 (https://regulomedb.
genes with COPD risk in the Tatar population from org), PolyPhen-2 prediction of functional effects of human
Russia . In this study, we aimed to assess the association nsSNPs (http://genetics.bwh.harvard.edu/pph2/), and
[26]
of single nucleotide polymorphisms (SNPs) of IL19, IL20, GTExportal (http://www.gtexportal.org/). According to
Volume 1 Issue 1 (2022) 2 https://doi.org/10.36922/gtm.v1i1.91