Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease

Am J Respir Crit Care Med. 2009 May 1;179(9):835-42. doi: 10.1164/rccm.200809-1472OC. Epub 2009 Feb 12.


Rationale: Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood.

Objectives: 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.

Measurements and main 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.

Publication types

  • Multicenter Study

MeSH terms

  • Angiopoietin-1 / genetics
  • Aromatase / genetics
  • Calcium-Binding Proteins / genetics
  • Case-Control Studies
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / genetics
  • Estradiol / blood
  • Estrogen Receptor alpha / genetics
  • Female
  • Genotype
  • Humans
  • Hypertension, Portal / genetics*
  • Liver Diseases / complications*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptors, Retinoic Acid / genetics
  • Risk Factors


  • Angiopoietin-1
  • Calcium-Binding Proteins
  • Estrogen Receptor alpha
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Estradiol
  • Aromatase
  • Cyclic Nucleotide Phosphodiesterases, Type 5