Effect of SNPs in HSP Family Genes, Variation in the mRNA and Intracellular Hsp Levels in COPD Secondary to Tobacco Smoking and Biomass-Burning Smoke.

Enrique Ambrocio-Ortiz,Alejandra Ramírez-Venegas,Gloria Pérez-Rubio,Alma D Del Angel-Pablo,Ramcés Falfán-Valencia,Rafael Hernández-Zenteno,Edgar Abarca-Rojano,Martha E Pérez-Rodríguez,Ana M Salazar

doi:10.3389/fgene.2019.01307

Abstract

Heat shock proteins (HSP) genes are a superfamily responsible for encoding highly conserved proteins that are important for antigen presentation, immune response regulation, and cellular housekeeping processes. These proteins can be increased by cellular stress related to pollution, for example, smoke from biomass burning and/or tobacco smoking. Single nucleotide polymorphisms (SNPs) in these genes could affect the levels of their proteins, as well as the susceptibility to developing lung diseases, such as chronic obstructive pulmonary disease (COPD), related to the exposure to environmental factors. Methods: The subjects included were organized into two comparison groups: 1,103 smokers (COPD patients, COPD-S = 360; smokers without COPD, SWOC = 743) and 442 never-smokers who were chronically exposed to biomass smoke (COPD patients, COPD-BS = 244; exposed without COPD, BBES = 198). Eight SNPs in three HSP genes were selected and genotyped: four in HSPA1A, two in HSPA1B, and two in HSPA1L. Sputum expectoration was induced to obtain pulmonary cells and relative quantification of mRNA expression. Subsequently, the intracellular protein levels of total Hsp27, phosphorylated Hsp27 (Hsp27p), Hsp60, and Hsp70 were measured in a sample of 148 individuals selected based on genotypes. Results: In the smokers’ group, by a dominant model analysis, we found associations between rs1008438 (CA+AA; p = 0.006, OR = 1.52), rs6457452 (CT+TT; p = 0.000015, OR = 1.99), and rs2763979 (CT+TT; p = 0.007, OR = 1.60) and the risk to COPD. Among those exposed to biomass-burning smoke, only rs1008438 (CA+AA; p < 0.01, OR = 2.84) was associated. Additionally, rs1008438 was associated with disease severity in the COPD-S group (AA; p = 0.02, OR = 2.09). An increase in the relative expression level of HSPA1A was found (12-fold change) in the COPD-BS over the BBES group. Differences in Hsp27 and Hsp60 proteins levels were found (p < 0.05) in the comparison of COPD-S vs. SWOC. Among biomass-burning smoke-exposed subjects, differences in the levels of all proteins (p < 0.05) were detected. Conclusion: SNPs in HSP genes are associated with the risk of COPD and severe forms of the disease. Differences in the intracellular Hsp levels are altered depending on the exposition source.

Highlights

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease; its main characteristic is progressive respiratory airways obstruction related to a chronic inflammatory response against noxious particles [Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2013; Montes de Oca et al, 2015]
Medians from three repetitions are presented with standard deviations (SDs). This is the first study in the Mexican mestizo population to examine the genetic susceptibility between COPD and HSP family genes, and it is the first to include mRNA levels from induced sputum cells and serum protein levels
Among the SWOC group, similar proportions of men and women (~50%) were observed, whereas the COPD secondary to smoking (COPD-S) group had a greater percentage of men (> 70%)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease; its main characteristic is progressive respiratory airways obstruction related to a chronic inflammatory response against noxious particles [Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2013; Montes de Oca et al, 2015]. Different risk factors have been described, including environmental and intrinsic ones [Menezes et al, 2005; Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2013]. The environmental risk factors include smoking (OMS | Tabaco, 2015) and chronic exposure to biomass-burning smoke (BBS) (Raj, 2014), while all the characteristics of the patients themselves are considered intrinsic factors (age, sex, individual genetic constitution) [Sørheim et al, 2010; Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2013]. 10 million people worldwide are smokers, and 80% live in emergent countries. There are no reports or monitoring of BBS, so the information about this risk factor is limited. It is known that ~30% of COPD cases are secondary to BBS exposure, with women being more affected than men (Ramírez-Venegas et al, 2006; Camp et al, 2014)

Methods

Results

Conclusion