Identification of candidate genes in scleroderma-related pulmonary arterial hypertension
Identification of candidate genes in scleroderma-related pulmonary arterial hypertension
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DOI：
10.1016/j.trsl.2007.12.010
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发表时间：
2008-04-01
影响因子：
7.8
通讯作者：
Hassoun, Paul M.
中科院分区：
文献类型：
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作者：
Grigoryev, Dmitry N.;Mathai, Stephen C.;Hassoun, Paul M.
我们推测，通过特发性肺动脉高压患者外周血单个核细胞(PBMC)的表达谱鉴定的肺动脉高压相关基因也可以在硬皮病合并PAH患者的PBMCs(PAH-SSC)中鉴定。采用HG_U133A_2.0 GeneChips基因芯片对9例PAH患者、10例PAH-SSC患者和5例健康对照的PBMC进行基因表达谱分析，并用RMA/GCOS_1.4/SAM_1.21数据分析流水线进行处理。通过功能状态和血流动力学测量来评估连续患者的疾病严重程度。用PAH严重程度分层分析表达谱，并用实时聚合酶链式反应(PCR)验证识别的候选基因。PAH-SSC患者PBMC的转录水平与PAH-SSC患者PMBC的转录水平高度相似。PBMC基因表达模式与右房压(RA)和心脏指数(0)显著相关，这是已知的预测PAH患者生存的指标。RA和CI的阵列分层确定了364个与PAH相关的候选基因。基因本体论(GO)分析显示根据PAH的严重程度，血管生成基因发生了显著(Z(Score)>；1.96)改变：实时定量聚合酶链式反应证实，与重度PAH和健康对照组相比，轻度PAH患者的基质金属蛋白酶9(MMP9)和血管内皮生长因子(VEGF)显著上调。这些数据表明，PAH-SSC患者的PBMC具有明显的转录表达。此外，我们的研究结果表明，血管生成相关基因的表达与PAH-SSC患者的PAH严重程度有关。破译参与血管重塑和PAH发展的基因的作用，可能会揭示这种毁灭性疾病的新治疗靶点。
We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from scleroderma patients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from I PAH (n = 9), PAH-SSc (n = 10) patients, and healthy controls (n = 5) were generated using HG_U133A_2.0 GeneChips and were processed by the RMA/GCOS_1.4/SAM_1.21 data analysis pipeline. Disease severity in consecutive patients was assessed by functional status and hemodynamic measurements. The expression profiles were analyzed using PAH severity-stratification, and identified candidate genes were validated with real-time polymerase chain reaction (PCR). Transcriptomics of PBMCs from IPAH patients was highly comparable with that of PMBCs from PAH-SSc patients. The PBMC gene expression patterns significantly correlate with right atrium pressure (RA) and cardiac index (0), which are known predictors of survival in PAH. Array stratification by RA and CI identified 364 PAH-associated candidate genes. Gene ontology (GO) analysis revealed significant (Z(score) > 1.96) alterations in angiogenesis genes according to PAH severity: matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF) were significantly upregulated in mild as compared with severe PAH and healthy controls, as confirmed by real-time PCR. These data demonstrate that PBMCs from patients with PAH-SSc carry distinct transcriptional expression. Furthermore, our findings suggest an association between angiogenesis-related gene expression and severity of PAH in PAH-SSc patients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.