Roberts Kari E, Fallon Michael B, Krowka Michael J, Brown Robert S, Trotter James F, Peter Inga, Tighiouart Hocine, Knowles James A, Rabinowitz Daniel, Benza Raymond L, Badesch David B, Taichman Darren B, Horn Evelyn M, Zacks Steven, Kaplowitz Neil, Kawut Steven M
Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Am J Respir Crit Care Med. 2009 May 1;179(9):835-42. doi: 10.1164/rccm.200809-1472OC. Epub 2009 Feb 12.
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.
6%的肝移植候选者会发生门肺高压（PPHTN）。这种门静脉高压并发症的发病机制尚不清楚。
确定晚期肝病患者发生PPHTN的遗传风险因素。
我们对门静脉高压患者进行了一项多中心病例对照研究。病例组的平均肺动脉压>25 mmHg，肺血管阻力>240 dynes·s⁻¹·cm⁻⁵，肺毛细血管楔压≤15 mmHg。对照组经胸超声心动图显示右心室收缩压<40 mmHg（如果是估算值）且右侧心脏形态正常。我们对每位患者的93个候选基因中的1079个常见单核苷酸多态性（SNP）进行了基因分型。
研究样本包括31例病例和104例对照。15个候选基因中的29个SNP与PPHTN风险相关（P<0.05）。编码雌激素受体1、芳香化酶、磷酸二酯酶5、血管生成素1和钙结合蛋白A4的基因中的多个SNP与PPHTN风险相关。芳香化酶SNP之一与血浆雌二醇水平的关联支持了其生物学相关性。
雌激素信号传导和细胞生长调节因子的基因变异与PPHTN风险相关。这些生物学途径可能阐明某些重症肝病患者发生PPHTN的机制。
