Abstract
BackgroundPulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.MethodsIn patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.Results580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69 years, mean FEV1 50% predicted, mean RVSP 44 mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6 mmHg respectively, compared to 43.2 mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a 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).ConclusionsThe NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.
Highlights
Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD)
We hypothesised that genetic variation in genes encoding mediators acting on pulmonary vessels alters right ventricular systolic pressure (RVSP) in patients with COPD, even after adjustment for clinical factors associated with elevated RVSP
Considering potential links between COPD severity and PH, we examined the effect of SNPs in relation to respiratory function tests
Summary
Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. Vascular remodelling is the main pathological feature in PH and is mediated via vasoactive molecules [4] Genes encoding these mediators contain genetic polymorphisms that potentially affect their function and could influence PH in COPD [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. We hypothesised that genetic variation in genes encoding mediators acting on pulmonary vessels alters right ventricular systolic pressure (RVSP) in patients with COPD, even after adjustment for clinical factors associated with elevated RVSP. We selected variants previously associated with vascular disease, in vasoactive mediators of biological importance in pulmonary hypertension
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