Cystic FibrosisNCT00804583
Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease
An observational study of Cystic Fibrosis and Liver Disease, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- Cystic Fibrosis, Liver Disease
- How many people
- 154 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2004to Jul 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: CF and liver disease
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599
About this study
Official title: Genetic Modifiers of CF Liver Disease
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.
Read the 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.
- Conditions
- Cystic Fibrosis, Liver Disease
- Keywords
- Cystic Fibrosis, Liver Disease, Genetic Modifiers
- Medical subject headings
- Cystic Fibrosis, Liver Diseases
What is being measured
The primary outcome is the main question the study is designed to answer.
This is not an interventional study
Measured: One Year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2008 (estimated)
- Study startMar 2004
- Primary completionJul 2028 (estimated)
- Study completionJul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 154 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Cystic Fibrosis Foundation
- Responsible party
- Sponsor
- Investigators
- Wanda K O'Neal, PhD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00804583
- Sponsor's protocol ID
- 01-1421
- Other IDs
- R01DK066368
- Status last verified
- Oct 2026
- First submitted
- 8 Dec 2008
- Last updated
- 3 Nov 2026
- Results posted
- No
- Data monitoring committee
- No
Publications
Mencin A, Seki E, Osawa Y, Kodama Y, De Minicis S, Knowles M, Brenner DA. Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis. Hepatology. 2007 Nov;46(5):1443-52. doi: 10.1002/hep.21832.
PubMed 17668872Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M Jr, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemkova D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR; Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009 Sep 9;302(10):1076-83. doi: 10.1001/jama.2009.1295.
PubMed 19738092Friedman, 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.
Sun L, Rommens JM, Corvol H, Li W, Li X, Chiang TA, Lin F, Dorfman R, Busson PF, Parekh RV, Zelenika D, Blackman SM, Corey M, Doshi VK, Henderson L, Naughton KM, O'Neal WK, Pace RG, Stonebraker JR, Wood SD, Wright FA, Zielenski J, Clement A, Drumm ML, Boelle PY, Cutting GR, Knowles MR, Durie PR, Strug LJ. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet. 2012 May;44(5):562-9. doi: 10.1038/ng.2221.
PubMed 22466613Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012 Dec 1;2(12):a009548. doi: 10.1101/cshperspect.a009548.
PubMed 23209180Blackman SM, Commander CW, Watson C, Arcara KM, Strug LJ, Stonebraker JR, Wright FA, Rommens JM, Sun L, Pace RG, Norris SA, Durie PR, Drumm ML, Knowles MR, Cutting GR. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes. 2013 Oct;62(10):3627-35. doi: 10.2337/db13-0510. Epub 2013 May 13.
PubMed 23670970Stonebraker JR, Ooi CY, Pace RG, Corvol H, Knowles MR, Durie PR, Ling SC. Features of Severe Liver Disease With Portal Hypertension in Patients With Cystic Fibrosis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1207-1215.e3. doi: 10.1016/j.cgh.2016.03.041. Epub 2016 Apr 5.
PubMed 27062904Polineni D, Piccorelli AV, Hannah WB, Dalrymple SN, Pace RG, Durie PR, Ling SC, Knowles MR, Stonebraker JR. Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population. PLoS One. 2018 Oct 11;13(10):e0205257. doi: 10.1371/journal.pone.0205257. eCollection 2018.
PubMed 30307979Raraigh KS, Aksit MA, Hetrick K, Pace RG, Ling H, O'Neal W, Blue E, Zhou YH, Bamshad MJ, Blackman SM, Gibson RL, Knowles MR, Cutting GR. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. doi: 10.1016/j.jcf.2021.10.011. Epub 2021 Nov 12.
PubMed 34782259Rosenfeld M, Faino AV, Onchiri F, Aksit MA, Blackman SM, Blue EE, Collaco JM, Gordon WW, Pace RG, Raraigh KS, Zhou YH, Cutting GR, Knowles MR, Bamshad MJ, Gibson RL. Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis. J Cyst Fibros. 2022 Jan;21(1):40-44. doi: 10.1016/j.jcf.2021.07.020. Epub 2021 Aug 13.
PubMed 34393091
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetic Modifiers of CF Liver Disease
- ClinicalTrials.gov ID
- NCT00804583
- Acronym / sponsor ID
- 01-1421
- Conditions
- Cystic Fibrosis, Liver Disease
- Keywords
- Cystic Fibrosis, Liver Disease, Genetic Modifiers
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 154 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Cystic Fibrosis Foundation
- Study start
- Mar 2004
- Primary completion
- Jul 2028 (estimated)
- Study completion
- Jul 2028 (estimated)
- First posted
- 9 Dec 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- CF and liver disease
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (8 listed)
- History of Alcohol Abuse
- History of Biliary Atresia
- History of Clinically Significant Hepatitis Infection
- History of Hepatic Vein Thrombosis
- History of Liver Cancer
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
This is not an interventional study
Time frame: One Year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2026.
- Background: PubMed 17668872Mencin A, Seki E, Osawa Y, Kodama Y, De Minicis S, Knowles M, Brenner DA. Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis. Hepatology. 2007 Nov;46(5):1443-52. doi: 10.1002/hep.21832.
- Background: PubMed 19738092Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M Jr, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemkova D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR; Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009 Sep 9;302(10):1076-83. doi: 10.1001/jama.2009.1295.
- BackgroundFriedman, 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.
- BackgroundFriedman, 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.
- Background: PubMed 22466613Sun L, Rommens JM, Corvol H, Li W, Li X, Chiang TA, Lin F, Dorfman R, Busson PF, Parekh RV, Zelenika D, Blackman SM, Corey M, Doshi VK, Henderson L, Naughton KM, O'Neal WK, Pace RG, Stonebraker JR, Wood SD, Wright FA, Zielenski J, Clement A, Drumm ML, Boelle PY, Cutting GR, Knowles MR, Durie PR, Strug LJ. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet. 2012 May;44(5):562-9. doi: 10.1038/ng.2221.
- Background: PubMed 23209180Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012 Dec 1;2(12):a009548. doi: 10.1101/cshperspect.a009548.
- Background: PubMed 23670970Blackman SM, Commander CW, Watson C, Arcara KM, Strug LJ, Stonebraker JR, Wright FA, Rommens JM, Sun L, Pace RG, Norris SA, Durie PR, Drumm ML, Knowles MR, Cutting GR. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes. 2013 Oct;62(10):3627-35. doi: 10.2337/db13-0510. Epub 2013 May 13.
- Background: PubMed 27062904Stonebraker JR, Ooi CY, Pace RG, Corvol H, Knowles MR, Durie PR, Ling SC. Features of Severe Liver Disease With Portal Hypertension in Patients With Cystic Fibrosis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1207-1215.e3. doi: 10.1016/j.cgh.2016.03.041. Epub 2016 Apr 5.
- Background: PubMed 30307979Polineni D, Piccorelli AV, Hannah WB, Dalrymple SN, Pace RG, Durie PR, Ling SC, Knowles MR, Stonebraker JR. Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population. PLoS One. 2018 Oct 11;13(10):e0205257. doi: 10.1371/journal.pone.0205257. eCollection 2018.
- Background: PubMed 34782259Raraigh KS, Aksit MA, Hetrick K, Pace RG, Ling H, O'Neal W, Blue E, Zhou YH, Bamshad MJ, Blackman SM, Gibson RL, Knowles MR, Cutting GR. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. doi: 10.1016/j.jcf.2021.10.011. Epub 2021 Nov 12.
- Background: PubMed 34393091Rosenfeld M, Faino AV, Onchiri F, Aksit MA, Blackman SM, Blue EE, Collaco JM, Gordon WW, Pace RG, Raraigh KS, Zhou YH, Cutting GR, Knowles MR, Bamshad MJ, Gibson RL. Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis. J Cyst Fibros. 2022 Jan;21(1):40-44. doi: 10.1016/j.jcf.2021.07.020. Epub 2021 Aug 13.
- Genetic Modifiers of Cystic Fibrosis Lung and Liver DiseaseLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wanda K O'Neal, PhD principal investigator
University of North Carolina, Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cystic Fibrosis and Liver Disease, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 3 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
This is not an interventional study (time frame: One Year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00804583, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2026.