Genetic polymorphisms of the serotonin transporter, but not the 2a receptor or nitric oxide synthetase, are associated with pulmonary hypertension in chronic obstructive pulmonary disease.
BACKGROUND
Pulmonary hypertension (PH) is prognosti- cally important in chronic obstructive pulmonary disease (COPD). Since PH only weakly correlates with hypoxemia, other factors must play a role.


OBJECTIVE
To investigate whether polymorphisms of the serotonin transporter (5HTT), serotonin-2a receptor (5HTR2a) and endothelial nitric oxide synthetase (eNOS) are related to PH in COPD.


METHODS
In 59 COPD patients who underwent right heart catheterization, 6-min walking distance, NYHA functional class, pulmonary function tests, blood gases and 5HTT, 5HTR2a and eNOS (4ab and T298C) polymorphisms were determined.


RESULTS
Forty-nine COPD patients in NYHA functional class III-IV were included. Ten were excluded due to comorbid causes of PH (mainly chronic thromboembolic). PH (mPAP > or =25 mm Hg) was present in 55% and usually mild, but out of proportion (mPAP > or =40 mm Hg) in 12%. Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%), and LL homozygote patients had more severe PH. In patients with out-of-proportion PH, the L-allelic frequency was even 75%. We found no association of 5HTR2a and eNOS polymorphism with PH in COPD.


CONCLUSIONS
In this COPD cohort we confirm that PH is frequent and usually mild, but out of proportion in a subgroup. We found a significant association of the L-allelic variant of 5HTT with PH overall and especially in out-of-proportion PH. These findings may point towards a role of the serotonin system in COPD-PH and warrant further studies.
Ulrich
Silvia
S
Clinics of Internal Medicine and Pulmonology, University Hospital Zürich, Zürich, Switzerland. silvia.ulrich@usz.ch
Hersberger
Martin
M
Fischler
Manuel
M
Nussbaumer-Ochsner
Yvonne
Y
Treder
Ursula
U
Russi
Erich W
EW
Speich
Rudolf
R
D000368:Aged; D006328:Cardiac Catheterization; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications*; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
D044402:Receptor, Serotonin, 5-HT2A; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III