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AzTrials

Cystic FibrosisNCT00037765

Gene Modifiers of Cystic Fibrosis Lung Disease

An observational study of Cystic Fibrosis and Lung Diseases, run by University of North Carolina, Chapel Hill at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

The purpose of this study is to examine genetic modifiers of the severity of cystic fibrosis lung disease. Read more about this study

Who is it for?
Ages Up to 100 years
Conditions the study is for
Cystic Fibrosis, Lung Diseases
How many people
600 participants
Where
1 siteUnited States
Study dates
Sep 2001to 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 Up to 100 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Study population: CF patients who have the same CFTR genetic background, i.e., homozygous F508del, and who are at the extremes of pulmonary phenotype, i.e., the most severe and mildest lung disease.

Who may be able to join

  • Diagnosed with CF

Who cannot join

  • Only those subjects who are not able to consent to this protocol

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Marsico Lung Institute

    Chapel Hill, North Carolina, 27599-7248

Other trials in United States

About this study

The purpose of this study is to examine genetic modifiers of the severity of cystic fibrosis lung disease.

Read the detailed description

BACKGROUND:

Cystic Fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in impaired chloride transport across epithelial cells. While many organs are involved, infection, inflammation and destruction of the lungs ultimately result in morbidity and mortality. There is an association between residual CFTR function and severity of disease, however there is great variability within specific mutations suggesting gene modifiers. Even though there are over 900 mutations in CFTR that are related to CF lung disease, F508 the most common one is represented in 70 percent of the American CF population. Thus, establishing a phenotype/genotype correlation using homozygote F508 patients is likely to identify genes that are responsible for a mild form of disease. Why is this important? Whereas since the identification of the gene CFTR a significant amount of knowledge has been accumulated on CFTR function and CF pathogenesis, the cure for CF (treated as a monogenic disease) has been elusive. Identification of genetic modifiers (that may explain why 10 percent of CF patients died before the age of 10, 1/3 before the age of 20 while 50 percent live over 32 years of age) should expand the therapeutic targets that may lead to shifting of the severe phenotypes to milder ones. Moreover, the approach outlined in this study may also result in a better understanding of CFTR and delta F508 biogenesis and function, as it may identify genes directly related to CFTR.

The study is in response to a Request for Applications titled "Genetic Modifiers of Single Gene Defect Diseases" released in August, 2000 and co-sponsored by the National Institute of Diabetes, Digestive, and Kidney Diseases.

DESIGN NARRATIVE:

Patients with cystic fibrosis (CF) display a wide range of disease severity, particularly in pulmonary phenotype. Although some of this variability can be attributed to specific mutations within the CFTR gene (allelic heterogeneity), much of this variability has not been adequately explained. The central hypothesis of the study is that much of the "severity" (or "mildness") of CF lung disease reflects the influence of non-CFTR "modifier" alleles (genes). The study is designed to identify associations between non-CFTR genes and the pulmonary phenotype. To accomplish this goal, studies will be conducted on 600 CF patients who have the same CFTR genetic background, i.e., homozygous deltaF508, and who are at the extremes of pulmonary phenotype, i.e., the most severe and mildest lung disease. Pulmonary disease severity (or mildness) will be quantitated by longitudinal lung function analysis with informative censoring. The overall strategy will be to test for the association of candidate modifier alleles (genes) with the severity (or mildness) of pulmonary disease. Key clinical features (gender; age-at-diagnosis; sweat chloride; nutrition; and respiratory microbiology) will be important variables in the overall analysis. Initially, the study will test candidate genes (n=200) that have been implicated in the pathophysiology of CF lung disease. A pooling strategy will be used to expedite the first rounds of testing. After pooling DNA from the "severe" patients, and pooling DNA from the mild patients, those genes (alleles) can be identified with the greatest association with phenotype. Follow-up genotyping in individual subjects will allow subgroup analyses (gender; age-at-diagnosis; nutrition; respiratory microbiology) for each gene, as well as more complex analyses to search for interaction among different alleles. Subsequent studies will involve genome-wide testing with single nucleotide polymorphisms (SNPs) to identify loci (and genes) that are not present in the initial list of candidate genes. Identification of genes that modulate the severity of the pulmonary phenotype will improve understanding of the pathophysiology of CF lung disease, and identify new targets for therapeutic intervention.

Medical subject headings
Cystic Fibrosis, Lung Diseases

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. This is not an interventional study.

    Not applicable. This is not an interventional study.

    Measured: This is not an interventional study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 May 2002 (estimated)
  2. Study startSep 2001
  3. Primary completionJul 2028 (estimated)
  4. Study completionJul 2028 (estimated)

Resources

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
600 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00037765
Sponsor's protocol ID
00-1420
Other IDs
5R01HL068890
Status last verified
Oct 2026
First submitted
20 May 2002
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 17668872
  • Vecchio-Pagan B, Blackman SM, Lee M, Atalar M, Pellicore MJ, Pace RG, Franca AL, Raraigh KS, Sharma N, Knowles MR, Cutting GR. Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits. Hum Genome Var. 2016 Nov 24;3:16038. doi: 10.1038/hgv.2016.38. eCollection 2016.

    PubMed 27917292
  • Collaco JM, Raraigh KS, Appel LJ, Cutting GR. Respiratory pathogens mediate the association between lung function and temperature in cystic fibrosis. J Cyst Fibros. 2016 Nov;15(6):794-801. doi: 10.1016/j.jcf.2016.05.012. Epub 2016 Jun 11.

    PubMed 27296562
  • Gong J, Wang F, Xiao B, Panjwani N, Lin F, Keenan K, Avolio J, Esmaeili M, Zhang L, He G, Soave D, Mastromatteo S, Baskurt Z, Kim S, O'Neal WK, Polineni D, Blackman SM, Corvol H, Cutting GR, Drumm M, Knowles MR, Rommens JM, Sun L, Strug LJ. Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci. PLoS Genet. 2019 Feb 26;15(2):e1008007. doi: 10.1371/journal.pgen.1008007. eCollection 2019 Feb.

    PubMed 30807572
  • Darrah RJ, Jacono FJ, Joshi N, Mitchell AL, Sattar A, Campanaro CK, Litman P, Frey J, Nethery DE, Barbato ES, Hodges CA, Corvol H, Cutting GR, Knowles MR, Strug LJ, Drumm ML. AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. J Cyst Fibros. 2019 Jan;18(1):127-134. doi: 10.1016/j.jcf.2018.05.013. Epub 2018 Jun 22.

    PubMed 29937318
  • Panjwani N, Xiao B, Xu L, Gong J, Keenan K, Lin F, He G, Baskurt Z, Kim S, Zhang L, Esmaeili M, Blackman S, Scherer SW, Corvol H, Drumm M, Knowles M, Cutting G, Rommens JM, Sun L, Strug LJ. Improving imputation in disease-relevant regions: lessons from cystic fibrosis. NPJ Genom Med. 2018 Mar 20;3:8. doi: 10.1038/s41525-018-0047-6. eCollection 2018.

    PubMed 29581887
  • Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR; Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med. 2005 Oct 6;353(14):1443-53. doi: 10.1056/NEJMoa051469.

    PubMed 16207846
  • Taylor-Cousar JL, Zariwala MA, Burch LH, Pace RG, Drumm ML, Calloway H, Fan H, Weston BW, Wright FA, Knowles MR; Gene Modifier Study Group. Histo-blood group gene polymorphisms as potential genetic modifiers of infection and cystic fibrosis lung disease severity. PLoS One. 2009;4(1):e4270. doi: 10.1371/journal.pone.0004270. Epub 2009 Jan 26.

    PubMed 19169360
  • Levy H, Murphy A, Zou F, Gerard C, Klanderman B, Schuemann B, Lazarus R, Garcia KC, Celedon JC, Drumm M, Dahmer M, Quasney M, Schneck K, Reske M, Knowles MR, Pier GB, Lange C, Weiss ST. IL1B polymorphisms modulate cystic fibrosis lung disease. Pediatr Pulmonol. 2009 Jun;44(6):580-93. doi: 10.1002/ppul.21026.

    PubMed 19431193
  • Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42. doi: 10.1038/nature07811. Epub 2009 Feb 25.

    PubMed 19242412
  • Li W, Sun L, Corey M, Zou F, Lee S, Cojocaru AL, Taylor C, Blackman SM, Stephenson A, Sandford AJ, Dorfman R, Drumm ML, Cutting GR, Knowles MR, Durie P, Wright FA, Strug LJ. Understanding the population structure of North American patients with cystic fibrosis. Clin Genet. 2011 Feb;79(2):136-46. doi: 10.1111/j.1399-0004.2010.01502.x.

    PubMed 20681990
  • Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, Sun L, Berthiaume Y, Cutler D, Cojocaru A, Collaco JM, Corey M, Dorfman R, Goddard K, Green D, Kent JW Jr, Lange EM, Lee S, Li W, Luo J, Mayhew GM, Naughton KM, Pace RG, Pare P, Rommens JM, Sandford A, Stonebraker JR, Sun W, Taylor C, Vanscoy LL, Zou F, Blangero J, Zielenski J, O'Neal WK, Drumm ML, Durie PR, Knowles MR, Cutting GR. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet. 2011 Jun;43(6):539-46. doi: 10.1038/ng.838. Epub 2011 May 22.

    PubMed 21602797
  • Schluchter MD, Konstan MW, Drumm ML, Yankaskas JR, Knowles MR. Classifying severity of cystic fibrosis lung disease using longitudinal pulmonary function data. Am J Respir Crit Care Med. 2006 Oct 1;174(7):780-6. doi: 10.1164/rccm.200512-1919OC. Epub 2006 Jul 20.

    PubMed 16858011
  • Knowles MR. Gene modifiers of lung disease. Curr Opin Pulm Med. 2006 Nov;12(6):416-21. doi: 10.1097/01.mcp.0000245707.59138.40.

    PubMed 17053491
  • Bartling TR, Drumm ML. Oxidative stress causes IL8 promoter hyperacetylation in cystic fibrosis airway cell models. Am J Respir Cell Mol Biol. 2009 Jan;40(1):58-65. doi: 10.1165/rcmb.2007-0464OC. Epub 2008 Jul 17.

    PubMed 18635816

Questions about this trial

What is this clinical trial studying?

An observational study of Cystic Fibrosis and Lung Diseases, 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 1 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: This is not an interventional study). 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 NCT00037765, which also lists 51 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.

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