Genetic Risk Factors for Portopulmonary Hypertension in Patients with Advanced Liver Disease

TLDR

Portopulmonary hypertension affects about 6 % of liver transplant candidates and its pathogenesis remains poorly understood. The study aimed to identify genetic risk factors for PPHTN in patients with advanced liver disease. A multicenter case‑control study genotyped 1,079 SNPs in 93 candidate genes in 31 PPHTN cases and 104 controls, defined by specific pulmonary hemodynamic criteria. Twenty‑nine SNPs in 15 genes—including estrogen receptor 1, aromatase, PDE5, angiopoietin 1, and calcium‑binding protein A4—were associated with PPHTN risk, with one aromatase variant linked to estradiol levels, indicating that estrogen signaling and cell‑growth pathways contribute to disease susceptibility.

Abstract

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