Endothelin-1 Gene Polymorphism in Chronic Obstructive Pulmonary Disease: A Case-Control Study

Abstract

Abstract Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a common multifactorial disease which has heterogeneous pathogenesis. The most important risk factor is smoking. In addition to many pathogenic mechanisms taking part in inflammatory process, Our study group does research on the relation of COPD with single nucleotide gene polymorphism at ET-1 gene. In the current studies there being a high ratio of Endotelin-1 (ET-1) in BAL liquid of COPD cases made researchers think ET-1 may have an important role in pathogenesis of COPD. Methods: This prospective case-control study included 89 patients admitted with COPD and 87 control patients. In our study, we search for the density of single nucleotide gene polymorphism (+134 insA/delA) in ET-1 gene in the 87 smoking COPD and 89 healthy cases. Allele ratio and genotype distribution, distribution amongst three genotype in the COPD patient and healthy control group was analyzed. In this study, for endothelin gene -3A/-4A (-138 insertion/deletion) polymorphism analysis, PCR-RFLP method was used. Results: In comparison with the healthy group, the COPD group has higher ratio of ET-1 gene (+134 insA/delA) polymorphism (p< 0,001). Conclusion: Endotelin-1 gene polymorphism (+134 insA/delA) significantly increased in the patients than healthy ones (p<0,013). Endothelin-1 gene polymorphism may be considered as a predictive genetic factor of COPD in Türkiye.

Keywords

• Endothelin-1
• Chronic Obstructive Pulmonary Disease
• Gene Polymorphism

References

1. 1. GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020; 8(6):585-96.
2. 2. Adeloye D, Song P, Zhu Y, Campbell H, Sheikh A, Rudan I; NIHR RESPIRE Global Respiratory Health Unit. Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir Med. 2022; 10(5):447-58.
3. 3. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J Glob Health. 2015; 5(2):020415.
4. 4. Lange P, Celli B, Agustí A, et al. Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease. N Engl J Med. 2015; 373(2):111-22.
5. 5. Burney P, Jarvis D, Perez-Padilla R. The global burden of chronic respiratory disease in adults. Int J Tuberc Lung Dis. 2015; 19:10-20.
6. 6. Wu X, Yuan B, López E, Bai C, Wang X. Gene polymorphisms and chronic obstructive pulmonary disease. J Cell Mol Med. 2014; 18(1):15-26.
7. 7. He XF, Wei W, Li JL, et al. Association between the XRCC3 T241M polymorphism and risk of cancer: evidence from 157 case-control studies. Gene. 2013; 523(1):10-19.
8. 8. Hingenboam T. Pulmonary hypertension and chronic obstructive pulmonary Disease. A Case for Treatment. Proc Am Thorac Soc. 2005; 2:12-19.

9. 9. Kaparianos A, Argyropoulou E, Efremidis G, Flordellis C, Spiropoulos K. Decline in FEV1 related to genetic polymorphisms (+138insA/delA and Lys198Asn) of the endothelin-1 gene in COPD. A pilot study. Eur Rev Med Pharmacol Sci. 2010;14(8):705-19.
10. 10. Spiropoulos K, Trakada G, Nikolaou E, et al. Endothelin-1 levels in the pathophysiology of chronic obstructive pulmonary disease and bronchial asthma. Respir Med. 2003;97(8): 983-89.
11. 11. Bacakoglu F, Atasever A, Ozhana MH, Gurgun C, Ozkilic H, Guzelant A. Plasma and bronchoalveolar lavage fluid levels of endothelin-1 in patients with Chronic Obstructive Pulmonary Disease and pulmonary hypertension. Respiration. 2003; 70:594-49.
12. 12. Sampsonas F, Antonacopoulou A, Spathas D, et al. Positive association between two polymorphic sites (+134 insA/delA and G198T) of the endothelin-1 gene and chronic obstructivepulmonary disease. A case-control study. Respir Med. 2010; 104(1):114-20.
13. 13. Battistini B, Dussault P. Biosynthesis, distribution and metabolism of endothelins in the pulmonary system. Pulm Pharmacol Ther. 1998; 11:79e88.
14. 14. Popowski K, Sperker B, Kroemer HK, John U, Laule M, Stangl K, Cascorbi I. Functional significance of a hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene. Pharmacogenetics. 2003; 13(8):445-51.
15. 15. Graham BL, Brusasco V, Burgos F, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017; 49:1600016.
16. 16. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med. 2019; 200:e70-e88.
17. 17. Denisov EN, Kots IaI, Bakhtiiarov RZ, Gumanova NG. [Effects of endotheline and nitric oxide on vascular tonicity in patients with chronic cardiac failure]. Ter Arkh. 2007; 79(12):44-47.
18. 18. Kwon YS, Chi SY, Shin HJ, et al. Plasma C-reactive protein and endothelin-1 level in patients with chronic obstructive pulmonary disease and pulmonary hypertension. J Korean Med Sci. 2010; 25(10):1487-91.
19. 19. Miller VM, Burnett JC Jr. Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries. Am J Physiol. 1992; 263(1 Pt 2):H103-8.
20. 20. Eddahibi S, Raffestin B, Clozel M, Levame M, Adnot S. Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats. Am J Physiol. 1995; 268(2 Pt 2):H828-35.
21. 21. Mullol J, Baraniuk JN, Logun C, Benfield T, Picado C, Shelhamer JH. Endothelin-1 induces GM-CSF, IL-6, IL-8 but not G-CSF release from a human epithelial cell line (BEAS-2B). Neuropeptides. 1996; 30(6):551-56.
22. 22. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax. 2001; 56(1):30-35.
23. 23. Carratu P, Scoditti C, Maniscalco M, et al. Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in COPD with pulmonary hypertension. BMC Pulm Med. 2008; 8:20.