Chung Wendy K, Deng Liyong, Carroll J Sheila, Mallory Nicole, Diamond Beverly, Rosenzweig Erika Berman, Barst Robyn J, Morse Jane H
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.
J Heart Lung Transplant. 2009 Apr;28(4):373-9. doi: 10.1016/j.healun.2009.01.016.
Pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often, idiopathic etiology. Genes can modify the risk of PAH: (1) monogenic disorders associated with PAH are incompletely penetrant, and (2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature.
We studied 247 patients with PAH, comprising 177 with idiopathic PAH (IPAH), 63 with PAH/connective tissue disease (CTD), and 7 with PAH associated with anorexigens. Patients were genotyped for 5 common polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis.
Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p = 0.005). Homozygotes for the 1166C allele (n = 13) were associated with an age at diagnosis 26 years later than those with A/A (n = 139) or A/C (n = 90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2.
The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH, suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.
肺动脉高压（PAH）是一种罕见的致命疾病，与单基因疾病、结缔组织病、接触食欲抑制剂有关，且通常病因不明。基因可改变PAH的风险：（1）与PAH相关的单基因疾病具有不完全外显率，（2）并非所有PAH风险增加的相关疾病患者都会发病。肾素血管紧张素醛固酮系统（RAAS）提供了一组候选基因，这些基因可能调节肺血管疾病，类似于其对肾血管和外周血管的作用。
我们研究了247例PAH患者，其中包括177例特发性PAH（IPAH）患者、63例PAH/结缔组织病（CTD）患者和7例与食欲抑制剂相关的PAH患者。对患者进行血管紧张素原（AGT）、血管紧张素转换酶（ACE）、心脏糜酶A（CMA1）、血管紧张素II 1型受体（AGTR1）和醛固酮合酶（CYP11B2）中5种常见多态性的基因分型。检测基因型与诊断年龄、诊断时的血流动力学参数和/或诊断时急性肺血管扩张试验反应之间的关联。
在IPAH中，AGTR1与诊断年龄之间存在关联（p = 0.005）。1166C等位基因纯合子（n = 13）的诊断年龄比A/A基因型（n = 139）或A/C基因型（n = 90）的患者晚26年。未发现AGT、ACE、CMA1或CYP11B2存在关联。
AGTR1中的1166C多态性似乎与IPAH患者诊断年龄较晚有关，这表明该途径可能参与了PAH中已知的生物学变异性。
