title: Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease.
abstract: 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.
authors.affiliation: Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA. kroberts@tuftsmedicalcenter.org
authors.forename: Kari E
authors.initials: KE
authors.lastname: Roberts
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krowka
authors.forename: Robert S
authors.initials: RS
authors.lastname: Brown
authors.forename: James F
authors.initials: JF
authors.lastname: Trotter
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: Hocine
authors.initials: H
authors.lastname: Tighiouart
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabinowitz
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.forename: David B
authors.initials: DB
authors.lastname: Badesch
authors.forename: Darren B
authors.initials: DB
authors.lastname: Taichman
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Horn
authors.forename: Steven
authors.initials: S
authors.lastname: Zacks
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kawut
mesh_terms: 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
chemical_list: 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