Published ahead of print on February 12, 2009, doi:10.1164/rccm.200809-1472OC
© 2009 American Thoracic Society doi: 10.1164/rccm.200809-1472OC
Genetic Risk Factors for Portopulmonary Hypertension in Patients with Advanced Liver Disease1 Department of Medicine, and 7 Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts; 2 Department of Medicine, University of Alabama, Birmingham, Alabama; 3 Department of Medicine, Mayo Clinic, Rochester, Minnesota; 4 Department of Medicine, College of Physicians and Surgeons, and 9 Department of Statistics, Columbia University, New York, New York; 5 Department of Medicine, University of Colorado, Denver, Colorado; 6 Department of Genetic and Genomic Sciences, Mount Sinai School of Medicine, New York, New York; 8 Department of Psychiatry and 12 Department of Medicine, University of Southern California, Los Angeles, California; 10 Department of Medicine and 13 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 11 Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Correspondence and requests for reprints should be addressed to Kari E. Roberts, M.D., Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, 800 Washington Street #257, Boston, MA 02111. E-mail:kroberts{at}tuftsmedicalcenter.org 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 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.
Key Words: genetic polymorphism • portal hypertension • hypertension, pulmonary
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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. 
