Abstract
Different biochemical pathways and cellular mechanisms play role in the pathogenesis of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). Alveolar hypoxia is not the only determinant of vascular remodeling, genetic factors are thought to have additive effects. We aimed to investigate the effects of endothelial nitric oxide synthase (eNOS A/B), angiotensin converting enzyme (ACE I/D) and serotonin transporter (5-HTT L/S) gene polymorphisms on development and severity of PH in COPD patients. 50 COPD patients without PH (group 1); 30 COPD patients with PH confirmed with echocardiography (group 2) and 49 healthy subjects (group 3) as control group were included to the study. eNOS A/B, ACE I/D and 5-HTT L/S gene polymorphisms and allele frequencies of COPD patients with and without PH and healthy subjects were determined. Functional parameters and echocardiographic measurements were recorded. Patients with PH were also assessed in two subgroups according to the severity of pulmonary arterial pressure (PAP). Significant differences among three groups in the distribution of 5-HTT genotype and allele frequency were present (respectively p = 0.002; p = 0.021). In group 2, LL and LS genotype rate was 93.3 % with a frequency of 71.2 % L allele and 28.3 % of S allele. 5-HTT LL genotype was present in 88.9 % of patients with PAP ≥50 mmHg significantly (p = 0.012). Other genotype distributions were not significantly different between two subgroups. The results of this study can suggest that COPD patients with L allele of 5-HTT may have higher risk for the development of PH and patients with LL genotype of 5-HTT may present higher PAP. We also demonstrated that eNOS and ACE gene polymorphisms were not associated with the development and severity of PH in our study population. Further studies with larger numbers of patients are needed to explore these relationships.
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References
Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2011). Global strategy for the diagnosis, management of chronic obstructive pulmonary disease. Revised
Agusti AGN, Noguera A, Sauleda J, Sala Pons EJ, Busquets X (2003) Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 21:34–360
Galiè N, Torbicki A, Barst R et al (2004) The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. Eur Heart J 25:2243–2278
Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731–736
Xue C, Johns RA (1996) Upregulation of nitric oxide synthase corelates temporally with onset of pulmonary vascular remodeling in the hypoxic rat. Hypertension 28:743–753
Studel W, Ichinose F, Huang PL et al (1997) Pulmonary vasoconstriction an hpertension in mice with targeted disruption of the endothelial nitric oxide synthase gene. Circ Res 81:34–41
Yildiz P, Oflaz H, Cine N et al (2003) Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD. Respir Med 97:1282–1288
Kanazawa H, Okamoto T, Hirata K, Yoshikawa J (2000) Deletion polymorphisms in angiotensin converting enzyme gene gene are associated with pulmonary hypertension evokde by exercise challenge in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 162:1235–1238
Ahsan A, Ram R, Baig AM et al (2004) ACE I allele and eNOS G allele crosstalk may have a role in chronic obstructive pulmonary disease. Clin Biochem 37:1037–1040
Olson TP, Snyder EM, Frantz RP et al (2007) Repeat length polymorphism of the serotonin transporter gene influences pulmonary artery pressure in heart failure. Am Heart J 153:426–432
Eddahibi S, Chaouat A, Morrell N et al (2003) Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease. Circulation 108:1839–1844
Miyahara K, Kawamoto T, Sase K, Yui Y, Toda K, Yang LX, Hattori R, Aoyama T, Yamamoto Y, Doi Y, Ogoshi S, Hashimoto K, Kawai C, Sasayama S, Shizuta Y (1994) Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene. Eur J Biochem 223:719–726
Lin MH, Tseng CH, Tseng CC, Huang CH, Chong CK, Tseng CP (2001) Real-time PCR for rapid genotyping of angiotensin-converting enzyme insertion/deletion polymorphism. Clin Biochem 34(8):661–666
Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38
Mossner R, Daniel S, Schmitt A, Albert D, Lesch KP (2001) Modulation of serotonin transporter function by interleukin-4. Life Sci 68:873–880
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF (1993) European Respiratory Society. Standardized lung function testing. Lung volumes and forced ventilatory flows. 1993 update. Eur Respir J 6:5–40
Wagner J, Clausen JL, Coates A et al (2005) Standardisation of the measurement of lung volumes. Eur Resp J 26:511–522
Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V (2005) Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 26(4):720–735
Pellegrino R, Viegi G, Brusasco V et al (2005) Interpretative startegies for lung function tests. Eur Respir J 26:948–968
Schiller NB, Shah PM, Crawford M et al (1989) Recommendations for quantification of left ventricle by two dimensional echocardiography. American Society of Echocardiography committee on standards, subcommitteeon quantitation of two dimensional echocardiograms. J Am Soc Echocardiogr 2:358–367
Parisi AF, Moynihan PF, Feldman CL et al (1979) Approaches to determination of left ventricular volume and ejection fraction by real time two-dimensional echocardiography. Clin Cardiol 2:257–263
Lanzarini L, Fontana A, Lucca E et al (2002) Noninvasive estimation of both systolic and diastolic pulmonary artery presuure from Doppler analysis of tricuspid regurgitant velocity spectrum in patients with chronic heart failure. Am Heart J 144:1087–1094
Berger M, Haimowitz A, van Tosch A et al (1985) Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 6:359–365
Yock PG, Popp RL (1984) Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 74:657–662
K Chemla D, Castelain V, Hervè P et al (2002) Hemodynamic evaluation of pulmonary hypertension. Eur Respir J 20:1314–1331
Lopez AD, Shibuya K, Rao C et al (2006) Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 27:397–412
Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J (2007) Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532–555
Gunen H, Hacievliyagil SS, Yetkin O et al (2008) Prevalence of COPD: first epidemiological study of a large region in Turkey. Eur J Intern Med 19:499–504
Carbone R, Bossone E, Bottino G et al (2005) Secondary pulmonary hypertension—diagnosis and management. Eur Rev Med Pharmacol Sci 9(6):331–342
Chaouat A, Naeije R, Weitzenblum E (2008) Pulmonary hypertension in COPD. Eur Respir J 32:1371–1385
Eddahibi S, Hanoun N, Lanfumey L et al (2000) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555–1562
Eddahibi S, Humbert M, Fadel E et al (2001) Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108:1141–1150
Eddahibi S, Fabre V, Boni C et al (1999) Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells relationship with the mitogenic action of serotonin. Circ Res 84:329–336
Busjahn A, Knoblauch H, Knoblauch M et al (1997) Angiotensin-converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions: a twin study. Hypertension 29:165–170
Cambien F, Poirjer O, Lecerf L et al (1992) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359:641–644
Raynolds MV, Bristow MR, Bush EW et al (1993) Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet 342:1073–1075
Nakai K, Itoh C, Miura Y et al (1994) Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation 90:2199–2202
Schunkert H, Hense HW, Holmer RS et al (1994) Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 330:1634–1638
Tkacova R, Joppa P, Stancak B, Salagovic J, Misikova S, Kalina I (2005) The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD. Wien Klin Wochenschr 117(5–6):210–214
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Sevinc Sarinc Ulasli—On leave of absence, Baskent University Faculty of Medicine, Department of Pulmonary Diseases, Ankara, Turkey.
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Ulasli, S.S., Eyuboglu, F.O., Verdi, H. et al. Associations between endothelial nitric oxide synthase A/B, angiotensin converting enzyme I/D and serotonin transporter L/S gene polymorphisms with pulmonary hypertension in COPD patients. Mol Biol Rep 40, 5625–5633 (2013). https://doi.org/10.1007/s11033-013-2664-6
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DOI: https://doi.org/10.1007/s11033-013-2664-6