Gene Modifiers of Cystic Fibrosis Lung Disease
Study Details
Study Description
Brief Summary
The purpose of this study is to examine genetic modifiers of the severity of cystic fibrosis lung disease.
| Condition or Disease | Intervention/Treatment | Phase |
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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.
Study Design
Outcome Measures
Primary Outcome Measures
- This is not an interventional study. [This is not an interventional study]
Not applicable. This is not an interventional study.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Diagnosed with CF
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Marsico Lung Institute | Chapel Hill | North Carolina | United States | 27599-7248 |
Sponsors and Collaborators
- University of North Carolina, Chapel Hill
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Michael Knowles, University of North Carolina
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Bartlett 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, Zemková 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.
- Blackman 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.
- 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.
- Corvol H, Blackman SM, Boëlle PY, Gallins PJ, Pace RG, Stonebraker JR, Accurso FJ, Clement A, Collaco JM, Dang H, Dang AT, Franca A, Gong J, Guillot L, Keenan K, Li W, Lin F, Patrone MV, Raraigh KS, Sun L, Zhou YH, O'Neal WK, Sontag MK, Levy H, Durie PR, Rommens JM, Drumm ML, Wright FA, Strug LJ, Cutting GR, Knowles MR. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382.
- Dang H, Gallins PJ, Pace RG, Guo XL, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, Knowles MR, O'Neal WK. Novel variation at chr11p13 associated with cystic fibrosis lung disease severity. Hum Genome Var. 2016 Jul 7;3:16020. doi: 10.1038/hgv.2016.20. eCollection 2016. Erratum in: Hum Genome Var. 2017 May 25;4:17016.
- Emond MJ, Louie T, Emerson J, Chong JX, Mathias RA, Knowles MR, Rieder MJ, Tabor HK, Nickerson DA, Barnes KC; NHLBI GO Exome Sequencing Project, Go L, Gibson RL, Bamshad MJ. Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. PLoS Genet. 2015 Jun 5;11(6):e1005273. doi: 10.1371/journal.pgen.1005273. eCollection 2015 Jun. Erratum in: PLoS Genet. 2015 Aug;11(8):e1005424.
- Guo X, Pace RG, Stonebraker JR, O'Neal WK, Knowles MR. Meconium ileus in cystic fibrosis is not linked to central repetitive region length variation in MUC1, MUC2, and MUC5AC. J Cyst Fibros. 2014 Dec;13(6):613-6. doi: 10.1016/j.jcf.2014.05.005. Epub 2014 Jun 8.
- Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG, Moskovitz J, Knowles MR, Durie PR, Drumm ML, Cutting GR. Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. PLoS Genet. 2012;8(3):e1002580. doi: 10.1371/journal.pgen.1002580. Epub 2012 Mar 15.
- Knowles 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.
- Miller MR, Soave D, Li W, Gong J, Pace RG, Boëlle PY, Cutting GR, Drumm ML, Knowles MR, Sun L, Rommens JM, Accurso F, Durie PR, Corvol H, Levy H, Sontag MK, Strug LJ. Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis. J Pediatr. 2015 May;166(5):1152-1157.e6. doi: 10.1016/j.jpeds.2015.01.044. Epub 2015 Mar 11.
- O'Neal WK, Gallins P, Pace RG, Dang H, Wolf WE, Jones LC, Guo X, Zhou YH, Madar V, Huang J, Liang L, Moffatt MF, Cutting GR, Drumm ML, Rommens JM, Strug LJ, Sun W, Stonebraker JR, Wright FA, Knowles MR. Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes. Am J Hum Genet. 2015 Feb 5;96(2):318-28. doi: 10.1016/j.ajhg.2014.12.022. Epub 2015 Jan 29.
- 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, Boëlle 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.
- Vecchio-Pagán 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. eCollection 2016.
- 00-1420
- 5R01HL068890