Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD)

Janet Shaw (2011). Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD) MPhil Thesis, School of Medicine, The University of Queensland.

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Author Janet Shaw
Thesis Title Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD)
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2011-10
Thesis type MPhil Thesis
Supervisor Associate Professor Ian Yang
Professor Kwun Fong
Associate Professor Rayleen Bowman
Associate Professor Paul Zimmerman
Total pages 115
Total colour pages 15
Total black and white pages 100
Language eng
Subjects 110203 Respiratory Diseases
110311 Medical Genetics (excl. Cancer Genetics)
Abstract/Summary This thesis examined 7 polymorphisms in 6 genes potentially involved in pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). These genes encode for molecules that mediate vascular tone. Background: PH in COPD involves vascular remodelling mediated by molecules that cause vasodilation or vasoconstriction. Genetic variation in these molecules may influence the pathogenesis of PH in COPD. Nitric oxide (NO) is a potent vasodilator synthesised by endothelial nitric oxide synthase (NOS3). Two polymorphisms, NOS3-Glu298Asp and NOS3 intron 4 VNTR (NOS3-VNTR), have been associated with coronary artery disease and with higher pulmonary artery pressures in COPD. Lower NO levels have been found in COPD patients with the NOS3-298Asp polymorphism suggesting a role in the aetiology of PH in COPD. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, a potent vasoconstrictor. The ACE insertion/deletion (ACE I/D) polymorphism has been linked to higher pulmonary vessel ACE levels and increased pulmonary vascular resistance which may increase the risk of developing PH. Endothelin-1 (EDN1) is a highly potent vasoconstrictor. The EDN1 Lys198Asn polymorphism has been associated with development and severity of COPD. Prostacyclin (PTGIS) is a potent vasodilator and inhibitor of platelet aggregation. The PTGIS C1117A polymorphism is thought to be a genetic marker of a functional mutation which changes expression of the PTGIS gene, leading to increased risk of PH in COPD. The serotonin transporter (SLC6A4) actively transports serotonin, a vasoconstrictor and mitogen of smooth muscle cells. The SLC6A4 L/S polymorphism affects the expression of the SLC6A4, and appears to determine the severity of PH in hypoxemic patients with COPD. Vascular endothelial growth factor (VEGFA) is a potent mediator of vascular regulation. VEGFA protein production has been significantly correlated to the VEGFA +405 G/C polymorphism suggesting an association with the development of PH. Aims: In patients with COPD: 1. To determine the frequency of these polymorphisms in COPD (NOS3-Glu298Asp, NOS3-VNTR, ACE I/D, EDN1 Lys198Asn, PTGIS C1117A, SLC6A4 L/S and VEGFA +405 G/C), and whether they are associated with right ventricular systolic pressure (RVSP, ≥40 mmHg) as determined by transthoracic echocardiography (278 patients). 2. To determine whether these polymorphisms are associated with RVSP, independently of clinical factors known to be associated with elevated RVSP (278 patients). 3. To determine the association of these genetic polymorphisms with a range of phenotypes of COPD (580 patients). Methods: 580 COPD patients, whose DNA is stored in the Tissue and Blood Bank of the Thoracic Research Laboratory, The Prince Charles Hospital were included. Genotypes were determined by PCR-RFLP or single base extension and correlated with RVSP, FEV1 % predicted, KCO % predicted, arterial PaO2, arterial PaCO2, smoking history, history of chronic bronchitis, body mass index (BMI) and patient demographics. Results: 341 patients had an echocardiogram performed, with 278 having a measurable RVSP. In this group (n=278) the mean age was 69 (±9) years, FEV1 % predicted was 50 (±21)%, KCO % predicted was 58 (±23)%, and RVSP was 44 (±13) mmHg and with a median smoking history of 50 pack-years. A major finding was that the NOS3-VNTR polymorphism was significantly associated with RVSP: mean RVSP for a/a and a/b genotypes were 52 and 47 mmHg (n=78) respectively, compared to a mean of 43 mmHg for b/b genotypes (n=199) (P=0.032, t-test). No associations were found between RVSP and any of the other polymorphisms studied. RVSP was inversely correlated to arterial PaO2, FEV1 % predicted, KCO % predicted, and FEV1/VC ratio. Older patients had a higher RVSP, as expected. Cumulative smoking history, chronic bronchitis, hypercapnia and BMI were unrelated to PH. There was no difference in RVSP between COPD patients with or without chronic bronchitis (99/278). In the 580 patients whom we related genotype / phenotype the ACE II or ID genotypes were associated with a significantly lower FEV1 % predicted, than the ACE DD genotype (P=0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P=0.031). Conclusions: The presence of the NOS3-VNTR polymorphism may be associated with higher RVSP in COPD patients. There were no statistically significant differences between genotypes and RVSP for the following SNPs: VEGFA +405 G/C, ACE I/D, SLC6A4 L/S, PTGIS C1117A, NOS3-Glu298Asp and EDN1 K198N. The frequency of these SNPs was determined in the 580 COPD patients and we found that the ACE genotypes may influence FEV1 % predicted, and NOS3 genotypes may influence KCO % predicted in these patients, suggesting a role in the pathogenesis of COPD. These genetic markers may contribute to disease severity and the variability in the development of PH in COPD patients. This study has contributed to the understanding of the pathogenic pathways involved in PH. Further study of these genes could lead to the development of prognostic and screening tools for more effective treatment for PH in COPD.
Keyword COPD
Pulmonary Hypertension
Genetic polymorphism
Additional Notes Colour pages: 28, 32, 34, 36-38, 40, 59-66 Landscape pages: 43-45, 111, 112

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Created: Mon, 18 Jun 2012, 18:06:59 EST by Janet Shaw on behalf of Library - Information Access Service