Deciphering the Genetic Basis of Portal Hypertension

破译门脉高压的遗传基础

• 批准号: 10398119
• 负责人: Silvia Vilarinho
• 金额: $ 16.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398119
• 关键词: Adult; Affect; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Biochemical; Biological Models; Blood; Blood Volume; Cessation of life; Childhood; Cirrhosis; Clinical; Collateral Circulation; Consensus; Coronary Arteriosclerosis; Counseling; Cryptogenic cirrhosis; DNA; Data; Deoxyguanosine kinase; Deoxyribonucleosides; Development; Diagnosis; Diagnostic; Diagnostic tests; Didanosine; Disease; Effectiveness; Extrahepatic; Family; Family member; General Population; Genes; Genetic; Genetic Counseling; Genetic Variation; Genotype; Germ Lines; Goals; Guanosine Triphosphate Phosphohydrolases; HIV; HIV Infections; Hepatic; Hepatology; Human Genetics; Human Genome; Hyperlipidemia; Hypertension; Impairment; In Vitro; Individual; Inferior; Inferior vena cava structure; Inherited; Label; Life; Link; Liver; Liver Cirrhosis; Liver diseases; Medical; Missense Mutation; Mitochondrial Matrix; Molecular; Mus; Mutate; Mutation; Parents; Pathogenesis; Pathologist; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Portal Hypertension; Portal Venous System; Prognosis; Purines; Recurrence; Registries; Reporting; Role; Sampling; Splenomegaly; Syndrome; Transaminases; Variant; base; biobank; clinical practice; disorder prevention; early onset; exome sequencing; genetic architecture; human genomics; infancy; insight; liver biopsy; liver development; loss of function mutation; mutant; new therapeutic target; next generation sequencing; novel; novel diagnostics; novel therapeutics; nucleoside analog; offspring; patient subsets; pediatric patients; personalized management; pressure; prototype; therapeutic target; trait

PROJECT’S SUMMARY/ABSTRACT Idiopathic liver disease remains a major challenge in both pediatric and adult hepatology, representing a high unmet medical need. Idiopathic portal hypertension (IPH), the focus of this proposal, is a prototype of a poorly understood liver disease. Portal hypertension is a silent clinical syndrome defined by portal venous system pressure that is at least 5 mmHg higher than the pressure in the inferior vena cava, but its complications represent the leading causes of liver-related death in the general population. IPH is diagnosed when a liver biopsy excludes cirrhosis, and all other known causes of portal hypertension have been ruled out. IPH has been reported in infancy and childhood, and in some families more than one individual is affected. Unexplained childhood phenotypes are excellent candidates to uncover mutations in genes not previously implicated in disease. Advances in human genetics and genomics through next generation sequencing have created tremendous opportunities for exploring how the human genome plays a role in disease. We demonstrated the utility of whole-exome sequencing (WES) in the diagnosis of pediatric liver diseases of unknown cause. Moreover, using WES, we identified a new Mendelian form of IPH due to a recurrent recessive mutation (p.N46S) in DGUOK, which encodes deoxyguanosine kinase. Interestingly, treatment of HIV-infected patients with the nucleoside analog didanosine causes non-cirrhotic portal hypertension in a subset of these patients and lowers DGUOK levels in vitro. Furthermore, we recently uncovered a novel bile acid synthesis disorder due to ACOX2 deficiency in a patient with a variant of IPH defined by incomplete septal cirrhosis; and our preliminary data shows that homozygous loss of function mutations in GIMAP5, encoding GTPase, IMAP family member 5, cause IPH. Based on these findings, we hypothesize that delineation of the genetic architecture of IPH will identify the genes and mechanisms underpinning inherited portal hypertension and these genes will also be relevant to a fraction of patients with common forms of portal hypertension. We will investigate this premise through the following three specific aims: (1) identify additional genes and pathways underlying unrecognized Mendelian forms of IPH; (2) determine the molecular mechanism(s) linking mutated genes (e.g. GIMAP5, ACOX2) to liver phenotype; (3) investigate the contribution of genetic variation in IPH-causing genes in drug-related non-cirrhotic portal hypertension in the general population. The study of rare Mendelian forms of common diseases, such as coronary artery disease, hyperlipidemia and hypertension, revealed to be highly informative regarding the general mechanisms of these conditions and development of new therapeutics. Thus, by investigating the genes implicated in rare cases of familial IPH, we expect to advance our understanding of portal hypertension pathogenesis, define new diagnostic tests for personalized management, identify novel therapeutic targets, and uncover novel pathways relevant to portal hypertension due to common liver diseases. !

项目总结/摘要 特发性肝病仍然是儿科和成人肝病学的主要挑战， 未满足的医疗需求特发性门静脉高压症（IPH），这一建议的重点，是一个原型， 了解肝病。门静脉高压症是一种以门静脉系统为特征的无症状临床综合征 压力至少比下腔静脉压力高5 mmHg，但其并发症 是一般人群中肝脏相关死亡的主要原因。IPH的诊断是当肝脏 活组织检查排除了肝硬化，所有其他已知的门静脉高压症的病因也被排除。IPH有 据报道，在婴儿期和儿童期，在一些家庭中不止一个人受到影响。不明原因 儿童期的表型是发现先前未涉及的基因突变的极好候选者， 疾病通过下一代测序，人类遗传学和基因组学的进步创造了 这是探索人类基因组如何在疾病中发挥作用的巨大机会。我们证明了 全外显子组测序（WES）在儿科不明原因肝病诊断中的应用 此外，使用WES，我们确定了一种新的孟德尔形式的IPH由于复发性隐性突变， （p.N46S），其编码脱氧鸟苷激酶。有趣的是，对艾滋病毒感染者的治疗 与核苷类似物去羟肌苷联用可导致这些患者中的一个亚组出现非硬化性门脉高压 并在体外降低DGUOK水平。此外，我们最近发现了一种新的胆汁酸合成障碍， 由于ACOX 2缺乏症，IPH变异型患者定义为不完全性间隔肝硬化; 初步数据显示，编码GT3、IMAP的GIMAP 5中的纯合功能缺失突变， 家庭成员5，导致IPH。基于这些发现，我们假设， IPH的结构将识别遗传性门脉高压的基因和机制 这些基因也将与一小部分具有常见形式门脉高压的患者相关， 高血压我们将通过以下三个具体目标来研究这一前提：（1）确定额外的 未被识别的孟德尔形式的IPH的基因和途径;（2）确定分子 将突变基因（例如GIMAP 5、ACOX 2）与肝脏表型联系起来的机制;（3）研究突变基因对肝脏表型的贡献。 在一般情况下，药物相关的非梗阻性门脉高压症中IPH引起基因的遗传变异 人口对罕见的孟德尔形式的常见疾病的研究，如冠状动脉疾病， 高脂血症和高血压，揭示了高度信息的一般机制，这些 条件和新疗法的发展。因此，通过研究与罕见病例有关的基因， 家族性IPH，我们希望能提高我们对门脉高压发病机制的认识， 个性化管理的诊断测试，确定新的治疗靶点，并发现新的途径 与常见肝病引起的门静脉高压症有关。 !

项目成果

Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency.

• DOI: 10.1007/s10875-022-01376-5
• 发表时间: 2023-02
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Korol, Cecilia B.;Belkaya, Serkan;Alsohime, Fahad;Lorenzo, Lazaro;Boisson-Dupuis, Stephanie;Brancale, Joseph;Neehus, Anna-Lena;Vilarinho, Silvia;Zobaida, Alsum;Halwani, Rabih;Al-Muhsen, Saleh;Casanova, Jean-Laurent;Jouanguy, Emmanuelle
• 通讯作者: Jouanguy, Emmanuelle

A single cell gene expression atlas of 28 human livers.

• DOI: 10.1016/j.jhep.2021.03.005
• 发表时间: 2021-07
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Brancale J;Vilarinho S
• 通讯作者: Vilarinho S

Genomic medicine for liver disease.

• DOI: 10.1002/hep.32364
• 发表时间: 2022-09
• 期刊: Hepatology (Baltimore, Md.)

Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study.

在一项前瞻性队列研究中，具有NAFLD的精益个体的基因组分析鉴定出单基因疾病。

• DOI: 10.1016/j.jhepr.2023.100692
• 发表时间: 2023-04
• 期刊: JHEP REPORTS
• 影响因子: 8.3
• 作者: Zheng, Melanie;Huang, Daniel Q.;Konkwo, Chigoziri;Agrawal, Saaket;Khera, Amit V.;Loomba, Rohit;Vilarinho, Silvia;Ajmera, Veeral
• 通讯作者: Ajmera, Veeral