Trial record 20 of 31 for:    Cystic Fibrosis | Open Studies | NIH, U.S. Fed

Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2015 by University of North Carolina, Chapel Hill
Cystic Fibrosis Foundation Therapeutics
Information provided by (Responsible Party):
Michael Knowles, MD, University of North Carolina, Chapel Hill Identifier:
First received: December 8, 2008
Last updated: February 3, 2015
Last verified: February 2015

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.

Cystic Fibrosis
Liver Disease

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genetic Modifiers of CF Liver Disease

Resource links provided by NLM:

Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • This is not an interventional study [ Time Frame: This is not an interventional study ] [ Designated as safety issue: No ]
    Not applicable. This is not an interventional study.

Biospecimen Retention:   Samples With DNA

A one time blood draw of 35 mls

Estimated Enrollment: 500
Study Start Date: March 2004
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
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.


Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00804583

Contact: Michael R Knowles, MD 919-966-6780
Contact: Beth Godwin, BA 919-966-6780

United States, North Carolina
The University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Michael R Knowles, MD    919-966-6780   
Contact: Beth Godwin, BA    919-966-6780   
Sponsors and Collaborators
University of North Carolina, Chapel Hill
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 Identifier: NCT00804583     History of Changes
Other Study ID Numbers: DK066368, R01DK066368, 5 R01DK066368
Study First Received: December 8, 2008
Last Updated: February 3, 2015
Health Authority: United States: Federal Government
United States: Institutional Review Board

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

Additional relevant MeSH terms:
Cystic Fibrosis
Liver Diseases
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases processed this record on August 27, 2015