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


METHODS
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.


RESULTS
580 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).


CONCLUSIONS
The 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.
Department of Thoracic Medicine, The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, QLD 4032, Australia. Janet_Shaw@health.qld.gov.au
Janet G
JG
Shaw
Annette G
AG
Dent
Linda H
LH
Passmore
Darryl J
DJ
Burstow
Rayleen V
RV
Bowman
Paul V
PV
Zimmerman
Kwun M
KM
Fong
Ian A
IA
Yang
D000368:Aged; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D005819:Genetic Markers; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D018598:Minisatellite Repeats; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D012720:Severity of Illness Index; D013147:Spirometry; D014463:Ultrasonography; D017725:Ventricular Pressure / Q000235:genetics*
D005819:Genetic Markers; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A