Increased HSP70 and TLR2 Gene Expression and Association of HSP70 rs6457452 Single Nucleotide Polymorphism with the Risk of Chronic Obstructive Pulmonary Disease in the Croatian Population.

Iva Hlapčić,Marija Grdić Rajković,Sanja Popović-Grle,Jelena Knežević,Asta Försti,Lada Rumora,Margareta Radić Antolic,Sanja Dabelić,Andrea Čeri

doi:10.3390/diagnostics11081412

Abstract

Heat shock protein 70 (Hsp70) engages Toll-like receptors (TLR) 2 and 4 when found in the extracellular compartment and contributes to inflammation in chronic obstructive pulmonary disease (COPD). Since there is growing evidence for the genetic risk factors for COPD, the gene expression of HSP70, TLR2 and TLR4 was determined, as well as the association between HSP70, TLR2 and TLR4 single nucleotide polymorphisms, (SNPs) and COPD. The gene expression was assessed in peripheral blood cells of 137 COPD patients and 95 controls by a quantitative polymerase chain reaction (qPCR), while a total of nine SNPs were genotyped by TaqMan allelic discrimination real-time PCR. HSP70 and TLR2 gene expression was increased in COPD patients compared to the controls, regardless of the disease severity and smoking status of participants. The rs6457452 SNP of HSP70 was associated with COPD, indicating the protective role of the T allele (OR = 0.46, 95% CI = 0.24–0.89, p = 0.022). Furthermore, COPD C/T heterozygotes showed a decreased HSP70 mRNA level compared to COPD C/C homozygotes. In conclusion, HSP70 and TLR2 may have a role in the pathogenesis of COPD, and the HSP70 rs6457452 variant might influence the genetic susceptibility to COPD in the Croatian population.

Highlights

Chronic obstructive pulmonary disease (COPD) is a multicomponent heterogeneous inflammatory disease characterized by persistent respiratory symptoms and airflow limitation [1]
This study showed that the gene expression of HSP70 and TLR2 was increased in COPD patients compared to controls
We found no association between plasma extracellular heat shock protein 70 (eHsp70) concentrations in COPD patients and selected HSP70, TLR2 and TLR4 polymorphisms

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a multicomponent heterogeneous inflammatory disease characterized by persistent respiratory symptoms and airflow limitation [1]. Tobacco exposure has been recognized as the main environmental risk factor for COPD [2], yet only 10–20% of smokers develop airway obstruction [3]. It is considered that the persistent low-grade inflammation in stable COPD might be caused by increased levels of many inflammatory mediators [5], reactive oxygen and nitrogen species [6], and pathogen-associated molecular patterns or damage-associated molecular patterns (DAMPs) such as extracellular heat shock protein 70 (eHsp70) [7,8,9]. Increased gene expression of HSP70 and its protein concentration was observed in lung tissues of COPD patients, and HSP70 mRNA levels were negatively correlated with lung function. In the study by Ambrocio-Ortiz et al, expression of HSP70 was examined in sputum, and they found a decrease in the COPD smoking group compared to controls who were mostly smokers [13]

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Conclusion