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Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease

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ClinicalTrials.gov Identifier: NCT00804583
Recruitment Status : Active, not recruiting
First Posted : December 9, 2008
Last Update Posted : August 31, 2017
Information provided by (Responsible Party):

Study Description
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.

Condition or disease
Cystic Fibrosis Liver Disease

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 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 Design

Study Type : Observational
Actual Enrollment : 154 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genetic Modifiers of CF Liver Disease
Study Start Date : March 2004
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :
  1. This is not an interventional study [ Time Frame: One Year ]

Biospecimen Retention:   Samples With DNA
A one time blood draw of 35 mls

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
CF and liver disease

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.

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00804583

United States, North Carolina
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Cystic Fibrosis Foundation Therapeutics
Principal Investigator: Michael R Knowles, MD University of North Carolina, Chapel Hill
More Information

Additional Information:
Friedman, K.J., S.C. Ling, E.M. Lange, M. Macek, Jr., A.J. Handler, R.G. Pace, F. Zou, D.R. Mack, S.C. Bell, G. Castaldo, F. Salvatore, U. Ozcelik, B. Tuemmler, M. Sinaasappel, J.L. Colombo, H. Kayserova, M. Phillips, J. Zielenski, L. Tsui, M.L. Drumm, L.M. Silverman, F.A Wright, P.R Durie, M.R. Knowles, Genetic Modifiers of Severe Liver Disease in Cystic Fibrosis, Pediatr Pulmonol Suppl 28:247:170, 2005.
Friedman, K.J., S.C. Ling, E.M. Lange, M. Macek, Jr., A.J. Handler, R.G. Pace, F. Zou, S.C. Bell, G. Castaldo, F. Salvatore, C. Colombo, M.J. Phillips, J. Zielenski, L.C. Tsui, M.L. Drumm, L.M. Silverman, F.A Wright, P.R Durie, M.R. Knowles, Genetic Modifiers of Severe Liver Disease in Cystic Fibrosis, 55th Annual Meeting The American Society of Human Genetics, Salt Lake City, UT, 395:2176/F, 2005.

Responsible Party: Michael Knowles, MD, Professor of Medicine, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT00804583     History of Changes
Other Study ID Numbers: R01DK066368 ( U.S. NIH Grant/Contract )
First Posted: December 9, 2008    Key Record Dates
Last Update Posted: August 31, 2017
Last Verified: August 2017

Keywords provided by Michael Knowles, MD, University of North Carolina, Chapel Hill:
Cystic Fibrosis
Liver Disease
Genetic Modifiers

Additional relevant MeSH terms:
Cystic Fibrosis
Liver Diseases
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases