Hernández-Gea Virginia, Campreciós Genís, Betancourt Fabián, Pérez-Campuzano Valeria, Seijo Susana, Díaz Alba, Gallego-Durán Rocío, Olivas Pol, Orts Lara, Magaz Marta, Baiges Anna, Turon Fanny, Sidorova Julia, Romero-Gómez Manuel, Lozano Juan-José, García-Pagán Juan Carlos
Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Catalonia, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.
Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Catalonia, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.
J Hepatol. 2021 Oct;75(4):924-934. doi: 10.1016/j.jhep.2021.05.014. Epub 2021 May 28.
BACKGROUND & AIMS: 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.
门静脉-肝窦血管病（PSVD）是一种病因不明的罕见肝脏血管疾病，可导致门静脉高压。它通常影响年轻人并缩短预期寿命。PSVD发展过程中涉及的失调通路尚不清楚，因此我们缺乏治愈性治疗方法。本研究的目的是通过基于综合网络的建模整合转录组学和临床数据，以揭示PSVD患者中改变的生物学过程。
我们从20例连续的PSVD患者、21例性别和年龄匹配的肝硬化患者以及13例组织学正常肝脏（HNL）患者（初始队列）中获取肝组织样本，并进行转录组分析。使用加权基因共表达网络分析对微阵列数据进行分析，以鉴定在PSVD患者中差异表达的高度相关基因簇。接下来，我们评估了PSVD患者中富集的分子通路以及PSVD患者中最显著富集通路的核心相关基因。我们的主要发现通过RNA测序在另一组PSVD、肝硬化和HNL患者（每组n = 8）中得到验证。
PSVD患者具有独特的基因谱，主要富集于涉及止血和凝血的经典通路，以及脂质代谢和氧化磷酸化通路。丝氨酸蛋白酶抑制剂家族（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连接的基因，可能在PSVD发病机制中起重要作用。
PSVD具有独特的转录组谱，我们已确定血管稳态相关通路的失调是疾病发展的主要致病事件。
门静脉-肝窦血管病是一种罕见但会缩短寿命的疾病，主要影响年轻人。了解其发展过程中涉及的失调通路将有助于识别新的治疗靶点和新的治疗方法。使用系统生物学方法，我们确定调节内皮功能和张力的通路可能是门静脉-肝窦血管病的驱动因素。
