# Deciphering the Genetic Basis of Portal Hypertension

> **NIH NIH K08** · YALE UNIVERSITY · 2021 · $169,884

## Abstract

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...

## Key facts

- **NIH application ID:** 10137911
- **Project number:** 5K08DK113109-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Silvia Vilarinho
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,884
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137911

## Citation

> US National Institutes of Health, RePORTER application 10137911, Deciphering the Genetic Basis of Portal Hypertension (5K08DK113109-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10137911. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*