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Abstract：
Porto-sinusoidal vascular disease (PSVD) is a rare vascular liver disease of unknown etiology that causes portal hypertension. It usually affects young individuals and shortens live expectancy. The deregulated pathways involved in PSVD development are unknown and therefore we lack curative treatments. The purpose of this study was to integrate transcriptomic and clinical data by comprehensive network-based modeling in order to uncover altered biological processes in patients with PSVD.
We obtained liver tissue samples from 20 consecutive patients with PSVD and 21 sex- and age-matched patients with cirrhosis and 13 histologically normal livers (HNL) (initial cohort) and performed transcriptomic analysis. Microarray data were analyzed using weighted gene correlation network analysis to identify clusters of highly correlated genes differently expressed in patients with PSVD. We next evaluated the molecular pathways enriched in patients with PSVD and the core-related genes from the most significantly enriched pathways in patients with PSVD. Our main findings were validated using RNA sequencing in a different cohort of PSVD, cirrhosis and HNL (n = 8 for each group).
Patients with PSVD have a distinctive genetic profile enriched mainly in canonical pathways involving hemostasis and coagulation but also lipid metabolism and oxidative phosphorylation. Serpin family (SERPINC1), the apolipoproteins (APOA, APOB, APOC), ATP synthases (ATP5G1, ATP5B), fibrinogen genes (FGB, FGA) and alpha-2-macroglobulin were identified as highly connective genes that may have an important role in PSVD pathogenesis.
PSVD has a unique transcriptomic profile and we have identified deregulation of pathways involved in vascular homeostasis as the main pathogenic event of disease development.
Porto-sinusoidal vascular disease is a rare but life-shortening disease that affects mainly young people. Knowledge of the disrupted pathways involved in its development will help to identify novel therapeutic targets and new treatments. Using a systems biology approach, we identify that pathways regulating endothelial function and tone may act as drivers of porto-sinusoidal vascular disease.
We obtained liver tissue samples from 20 consecutive patients with PSVD and 21 sex- and age-matched patients with cirrhosis and 13 histologically normal livers (HNL) (initial cohort) and performed transcriptomic analysis. Microarray data were analyzed using weighted gene correlation network analysis to identify clusters of highly correlated genes differently expressed in patients with PSVD. We next evaluated the molecular pathways enriched in patients with PSVD and the core-related genes from the most significantly enriched pathways in patients with PSVD. Our main findings were validated using RNA sequencing in a different cohort of PSVD, cirrhosis and HNL (n = 8 for each group).
Patients with PSVD have a distinctive genetic profile enriched mainly in canonical pathways involving hemostasis and coagulation but also lipid metabolism and oxidative phosphorylation. Serpin family (SERPINC1), the apolipoproteins (APOA, APOB, APOC), ATP synthases (ATP5G1, ATP5B), fibrinogen genes (FGB, FGA) and alpha-2-macroglobulin were identified as highly connective genes that may have an important role in PSVD pathogenesis.
PSVD has a unique transcriptomic profile and we have identified deregulation of pathways involved in vascular homeostasis as the main pathogenic event of disease development.
Porto-sinusoidal vascular disease is a rare but life-shortening disease that affects mainly young people. Knowledge of the disrupted pathways involved in its development will help to identify novel therapeutic targets and new treatments. Using a systems biology approach, we identify that pathways regulating endothelial function and tone may act as drivers of porto-sinusoidal vascular disease.
摘要：
波窦血管疾病（PSVD）是一种病因不明的罕见血管性肝病，可引起门脉高压。它通常影响年轻人并缩短预期寿命。参与PSVD发展的失调途径是未知的，因此我们缺乏治愈性治疗。这项研究的目的是通过基于网络的综合建模整合转录组和临床数据，以发现PSVD患者的生物学过程改变。
我们获得了20例连续PSVD患者和21例性别和年龄匹配的肝硬化患者和13例组织学正常肝脏（HNL）（初始队列）的肝组织样本，并进行了转录组学分析。使用加权基因相关网络分析对微阵列数据进行分析，以鉴定在PSVD患者中不同表达的高度相关基因的簇。我们接下来评估了PSVD患者中富集的分子通路和PSVD患者中最显著富集的通路中的核心相关基因。我们的主要发现在不同的PSVD队列中使用RNA测序进行了验证，肝硬化和HNL（每组n=8）。
PSVD患者具有独特的遗传特征，主要富集在涉及止血和凝血以及脂质代谢和氧化磷酸化的经典途径中。Serpin家族(SERPINC1),载脂蛋白(APOA，APOB,APOC)，ATP合酶（ATP5G1，ATP5B），纤维蛋白原基因(FGB，FGA）和α-2-巨球蛋白被鉴定为高度结缔组织基因，可能在PSVD发病机理中起重要作用。
PSVD具有独特的转录组特征，我们已经确定了与血管稳态有关的通路失调是疾病发展的主要致病事件。
窦口血管疾病是一种罕见但缩短寿命的疾病，主要影响年轻人。了解其发展过程中涉及的破坏途径将有助于确定新的治疗靶标和新的治疗方法。使用系统生物学方法，我们发现调节内皮功能和张力的通路可能是门窦血管疾病的驱动因素.
我们获得了20例连续PSVD患者和21例性别和年龄匹配的肝硬化患者和13例组织学正常肝脏（HNL）（初始队列）的肝组织样本，并进行了转录组学分析。使用加权基因相关网络分析对微阵列数据进行分析，以鉴定在PSVD患者中不同表达的高度相关基因的簇。我们接下来评估了PSVD患者中富集的分子通路和PSVD患者中最显著富集的通路中的核心相关基因。我们的主要发现在不同的PSVD队列中使用RNA测序进行了验证，肝硬化和HNL（每组n=8）。
PSVD患者具有独特的遗传特征，主要富集在涉及止血和凝血以及脂质代谢和氧化磷酸化的经典途径中。Serpin家族(SERPINC1),载脂蛋白(APOA，APOB,APOC)，ATP合酶（ATP5G1，ATP5B），纤维蛋白原基因(FGB，FGA）和α-2-巨球蛋白被鉴定为高度结缔组织基因，可能在PSVD发病机理中起重要作用。
PSVD具有独特的转录组特征，我们已经确定了与血管稳态有关的通路失调是疾病发展的主要致病事件。
窦口血管疾病是一种罕见但缩短寿命的疾病，主要影响年轻人。了解其发展过程中涉及的破坏途径将有助于确定新的治疗靶标和新的治疗方法。使用系统生物学方法，我们发现调节内皮功能和张力的通路可能是门窦血管疾病的驱动因素.
