Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease

Active, not recruiting

• Conditions: Cystic Fibrosis; Liver Disease

• Registration Number: NCT00804583
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

This study examines "modifier genes" that may play a role in the development of CF liver disease. Modifier genes are genes, other than the CF gene (CFTR), which may directly or indirectly have an affect on how the body responds to the conditions that develop as the result of the defective CFTR gene. Scientists have wondered why some patients with CF develop CF liver disease and why some patients with CF do not. To better understand the problem, this study was designed to examine the genetic makeup of CF patients who are considered to have severe liver disease to see if they can identify any modifier genes. Researchers will study blood samples, pulmonary function tests, and other medical information in hopes that a connection can be made between genetic make-up and how severe the liver disease is. The identification of modifier genes that influence disease severity may ultimately lead to a better understanding of CF liver disease, and may be useful in the development of new treatments.

Detailed Description

The clinical heterogeneity in cystic fibrosis (CF) is only partly explained by mutations in the CFTR gene. Most CF patients have evidence of liver dysfunction and focal biliary cirrhosis (fibrosis), and a subset of these patients (5-7%) progresses to severe liver disease (CFLD), as defined by portal hypertension and multilobular cirrhosis. The development of CFLD has no relationship to specific CFTR mutations or other biomarkers, and there is currently no way to identify which CF infants will develop severe liver disease.

The central hypothesis of this proposal is that the development of CFLD reflects the influence of non-CFTR "modifier" alleles (genes). This project is designed to identify associations between non-CFTR genes and CFLD, and test the biological effect of selected alleles on hepatic fibrosis in transgenic murine models. We hypothesize that polymorphisms in multiple genes, each with a conceptual or mechanistic link to liver disease, increase the risk for developing end-stage CF liver disease, and that interactions among these risk factors will define the pathophysiology of this disorder. To achieve our goals, we will study 400 CF patients with well-documented severe liver disease and portal hypertension, and 400 gender and genotype-matched CF patients \> age 15 years who have no evidence of CFLD. We propose to identify heritable risk factors for the development of CFLD by evaluation of functional sequence variants within, and single nucleotide polymorphisms associated with, multiple genes associated with CFLD pathogenesis. To test ("validate") the biological effects (impact) of selected genetic alleles on liver fibrosis, we will develop transgenic mice homozygous for DeltaF508 (DF508), who are also expressing an additional candidate gene modifier allele. Better definition of the complex genotypes that increase risk for severe liver disease in CF will allow early identification of CF infants predisposed to develop end-stage liver disease, and thereby allow testing of currently available therapies. Better understanding of the pathobiology of hepatic fibrosis in CF will identify novel targets to prevent (or reduce) the development of CFLD.

Study Timeline

• Study Start: 2004-03
• Study First Submitted: 2008-12-08
• Study First Submitted QC: 2008-12-08
• Study First Posted: 2008-12-09
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-22
• Last Update Posted: 2024-08-26
• Primary Completion: 2026-07
• Study Completion: 2026-07

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 154

Inclusion Criteria

• Volunteers with CF, regardless of genotype and age, who have "severe" liver disease with portal hypertension (big spleen, i.e. "splenomegaly" and/or presence of enlarged vessels in the esophagus, i.e. esophageal varices) may be eligible to participate. This would include any person who has been evaluated for a liver transplant, or has already received a liver transplant.

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Exclusion Criteria

• History of Alcohol Abuse
• History of Biliary Atresia
• History of Clinically Significant Hepatitis Infection
• History of Hepatic Vein Thrombosis
• History of Liver Cancer
• History of Portal Vein Thrombosis
• History of Clinically Significant use of total parenteral nutrition (TPN)
• History of Wilson's Disease

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
This is not an interventional study	One Year

Trial Locations

Locations (1)

The University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States