Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease.
BACKGROUND
Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood.


OBJECTIVE
To identify genetic risk factors for PPHTN in patients with advanced liver disease.


METHODS
We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes.s(-1).cm(-5), and pulmonary capillary wedge pressure < or =15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient.


RESULTS
The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P < 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels.


CONCLUSIONS
Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.
Roberts
Kari E
KE
Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA. kroberts@tuftsmedicalcenter.org
Fallon
Michael B
MB
Krowka
Michael J
MJ
Brown
Robert S
RS
Trotter
James F
JF
Peter
Inga
I
Tighiouart
Hocine
H
Knowles
James A
JA
Rabinowitz
Daniel
D
Benza
Raymond L
RL
Badesch
David B
DB
Taichman
Darren B
DB
Horn
Evelyn M
EM
Zacks
Steven
S
Kaplowitz
Neil
N
Kawut
Steven M
SM
D042683:Angiopoietin-1 / Q000235:genetics; D001141:Aromatase / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics*; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012307:Risk Factors
D042683:Angiopoietin-1; D002135:Calcium-Binding Proteins; D047628:Estrogen Receptor alpha; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D004958:Estradiol; D001141:Aromatase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5