Pulmonary hypertension in type I Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy
Pulmonary hypertension in type I Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy
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DOI：
10.1016/s1096-7192(02)00122-1
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发表时间：
2002-09-01
影响因子：
3.8
通讯作者：
Goldman, ME
中科院分区：
文献类型：
--
作者：
Mistry, PK;Sirrs, S;Goldman, ME
I型戈谢病（GD）被认为具有显著但无法解释的表型多样性。GD中可能发生重度肺动脉高压（PH），但其临床谱、决定因素或对酶替代疗法（ERT）+/-血管扩张剂的反应尚不清楚。对134例连续I型GD患者进行筛选，通过多普勒超声心动图估计右心室收缩压（RVSP）。94例患者接受ERT治疗，40例未接受治疗。八个额外的GD患者进行了研究，代表连续三级转诊严重PH。血管紧张素转换酶（ACE）基因多态性和酸性β-葡萄糖苷酶基因（GBA）突变的DNA分析确定。轻度无症状PH（RVSP > 35 < 50 mm Hg）在1型GD中普遍存在：未治疗患者中为30%，接受ERT的患者中为7.4%（P < 0.001）。脾切除术与严重危及生命的PH密切相关：所有重度PH（RVSP 50-130 mm Hg）患者均为无脾型，而RVSP < 50 mm Hg患者仅为31%（比值比[OR] 28.8，95% CI 1.6-531.6，P < 0.001）。重度PH患者的其他特征是对ERT的依从性差（4/9例患者）或无ERT（5/9例患者），有GD和PH同胞家族史（2/2例患者），ACE I等位基因过量（OR 2.3，95% CI 1.1-4.9，P = 0.034）和过量的非N370 S GBA突变（OR 6.0，95% CI 1.1-33，P = 0.003）。在4.6 +/- 4.0年（范围1-12年）随访期间，ERT血管扩张剂改善了重度PH; 3例患者最初考虑进行肺移植，但改善后不再是积极的移植候选者。我们的研究揭示了一个显着的易感性PH在I型GD。在存在其他遗传因素（非N370 S GBA突变、阳性家族史和ACE I基因多态性）和表观遗传修饰因子（即，无脾和女性）。应避免脾切除术，对于高风险患者，应开始ERT +/-血管扩张剂/香豆素。(C)2002 Elsevier Science（美国）。All rights reserved.
Type I Gaucher's disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT) +/- vasodilators is not known. One hundred and thirty-four consecutive patients with Type I GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid beta-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP > 35 < 50 mm Hg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P < 0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50-130 mm Hg) were asplenic compared to only 31% of patients with RVSP < 50 mm Hg (Odds ratio [OR] 28.8, 95% Cl 1.6-531.6, P < 0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1-4.9, P = 0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1-33, P = 0.003). Severe PH was ameliorated by ERT vasodilators during 4.6 +/- 4.0 yr (range 1-12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type I GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT +/- vasodilators/coumadin should be initiated. (C) 2002 Elsevier Science (USA). All rights reserved.