Gene Modifiers of Cystic Fibrosis Lung Disease

Cystic Fibrosis Clinical Trial

Official title:

Gene Modifiers of Cystic Fibrosis Lung Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00037765
• Other study ID #: 00-1420
• Secondary ID: 5R01HL068890
• Status: Active, not recruiting
• Start date: September 2001
• Est. completion date: July 2024

Study information

• Verified date: November 2023
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 600
• Est. completion date: July 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 100 Years

Eligibility

Inclusion Criteria:

• Diagnosed with CF

Exclusion criteria:

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Lung Diseases
• Pulmonary Fibrosis

Locations

Country	Name	City	State
United States	Marsico Lung Institute	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (51)

Aksit MA, Ling H, Pace RG, Raraigh KS, Onchiri F, Faino AV, Pagel K, Pugh E, Stilp AM, Sun Q, Blue EE, Wright FA, Zhou YH, Bamshad MJ, Gibson RL, Knowles MR, Cutting GR, Blackman SM; CF Genome Project. Pleiotropic modifiers of age-related diabetes and neo — View Citation

Aksit MA, Pace RG, Vecchio-Pagan B, Ling H, Rommens JM, Boelle PY, Guillot L, Raraigh KS, Pugh E, Zhang P, Strug LJ, Drumm ML, Knowles MR, Cutting GR, Corvol H, Blackman SM. Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With — View Citation

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, Zemkova D, Hannah WB, — View Citation

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. — View Citation

Bezzerri V, d'Adamo P, Rimessi A, Lanzara C, Crovella S, Nicolis E, Tamanini A, Athanasakis E, Tebon M, Bisoffi G, Drumm ML, Knowles MR, Pinton P, Gasparini P, Berton G, Cabrini G. Phospholipase C-beta3 is a key modulator of IL-8 expression in cystic fibr — View Citation

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):3627-3 — View Citation

Blackman SM, Hsu S, Ritter SE, Naughton KM, Wright FA, Drumm ML, Knowles MR, Cutting GR. A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis. Diabetologia. 2009 Sep;52(9):1858-65. doi: 10.1007/s0012 — View Citation

Collaco JM, Blackman SM, Raraigh KS, Corvol H, Rommens JM, Pace RG, Boelle PY, McGready J, Sosnay PR, Strug LJ, Knowles MR, Cutting GR. Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis. Am J Respir Crit Care Med. 2016 Dec 1;194(11):1 — View Citation

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. — View Citation

Corvol H, Blackman SM, Boelle 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, — View Citation

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.2 — View Citation

Dang H, Polineni D, Pace RG, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, O'Neal WK, Knowles MR. Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation. PLoS One. 2020 Nov 30;15(11):e0239189. doi: 10.1371/journa — View Citation

Darrah R, McKone E, O'Connor C, Rodgers C, Genatossio A, McNamara S, Gibson R, Stuart Elborn J, Ennis M, Gallagher CG, Kalsheker N, Aitken M, Wiese D, Dunn J, Smith P, Pace R, Londono D, Goddard KA, Knowles MR, Drumm ML. EDNRA variants associate with smoo — View Citation

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. — View Citation

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 modifie — View Citation

Eastman AC, Pace RG, Dang H, Aksit MA, Vecchio-Pagan B, Lam AN, O'Neal WK, Blackman SM, Knowles MR, Cutting GR. SLC26A9 SNP rs7512462 is not associated with lung disease severity or lung function response to ivacaftor in cystic fibrosis patients with G551 — View Citation

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 M — View Citation

Emond MJ, Louie T, Emerson J, Zhao W, Mathias RA, Knowles MR, Wright FA, Rieder MJ, Tabor HK, Nickerson DA, Barnes KC; National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project; Lung GO; Gibson RL, Bamshad MJ. Exome sequencing of extre — View Citation

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. — View Citation

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. Id — View Citation

Guo X, Pace RG, Stonebraker JR, Commander CW, Dang AT, Drumm ML, Harris A, Zou F, Swallow DM, Wright FA, O'Neal WK, Knowles MR. Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: significant association with MU — View Citation

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 — View Citation

Guo X, Zheng S, Dang H, Pace RG, Stonebraker JR, Jones CD, Boellmann F, Yuan G, Haridass P, Fedrigo O, Corcoran DL, Seibold MA, Ranade SS, Knowles MR, O'Neal WK, Voynow JA. Genome reference and sequence variation in the large repetitive central exon of hu — View Citation

Harris WT, Muhlebach MS, Oster RA, Knowles MR, Clancy JP, Noah TL. Plasma TGF-beta(1) in pediatric cystic fibrosis: potential biomarker of lung disease and response to therapy. Pediatr Pulmonol. 2011 Jul;46(7):688-95. doi: 10.1002/ppul.21430. Epub 2011 Fe — View Citation

Harris WT, Muhlebach MS, Oster RA, Knowles MR, Noah TL. Transforming growth factor-beta(1) in bronchoalveolar lavage fluid from children with cystic fibrosis. Pediatr Pulmonol. 2009 Nov;44(11):1057-64. doi: 10.1002/ppul.21079. — View Citation

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 — View Citation

Hillian AD, Londono D, Dunn JM, Goddard KA, Pace RG, Knowles MR, Drumm ML; CF Gene Modifier Study Group. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun. 2008 Sep;9(6):501-8. doi: 10.1038/gene.2008.42. Epub 2008 Jun 19 — View Citation

Kingston H, Stilp AM, Gordon W, Broome J, Gogarten SM, Ling H, Barnard J, Dugan-Perez S, Ellinor PT, Gabriel S, Germer S, Gibbs RA, Gupta N, Rice K, Smith AV, Zody MC; Cystic Fibrosis Genome Project; NHLBI Trans-Omics for Precision Medicine (TOPMed) Conso — View Citation

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. — View Citation

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. — View Citation

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 Pul — View Citation

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 fib — View Citation

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. — View Citation

Miller MR, Soave D, Li W, Gong J, Pace RG, Boelle 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 — View Citation

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 v — View Citation

Pandey JP, Namboodiri AM, Nietert PJ, Knowles MR, Pace RG, Pier GB. Immunoglobulin GM and KM allotypes are associated with antibody responses to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients. J Cyst Fibros. 2021 Nov;20(6 — View Citation

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. — View Citation

Polineni D, Dang H, Gallins PJ, Jones LC, Pace RG, Stonebraker JR, Commander LA, Krenicky JE, Zhou YH, Corvol H, Cutting GR, Drumm ML, Strug LJ, Boyle MP, Durie PR, Chmiel JF, Zou F, Wright FA, O'Neal WK, Knowles MR. Airway Mucosal Host Defense Is Key to — View Citation

Polineni 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 — View Citation

Raraigh 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 Fib — View Citation

Rosenfeld 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 cys — View Citation

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 — View Citation

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, Boe — View Citation

Sun Q, Liu W, Rosen JD, Huang L, Pace RG, Dang H, Gallins PJ, Blue EE, Ling H, Corvol H, Strug LJ, Bamshad MJ, Gibson RL, Pugh EW, Blackman SM, Cutting GR, O'Neal WK, Zhou YH, Wright FA, Knowles MR, Wen J, Li Y; Cystic Fibrosis Genome Project. Leveraging — View Citation

Sun Q, Yang Y, Rosen JD, Jiang MZ, Chen J, Liu W, Wen J, Raffield LM, Pace RG, Zhou YH, Wright FA, Blackman SM, Bamshad MJ, Gibson RL, Cutting GR, Knowles MR, Schrider DR, Fuchsberger C, Li Y. MagicalRsq: Machine-learning-based genotype imputation quality — View Citation

Taylor C, Commander CW, Collaco JM, Strug LJ, Li W, Wright FA, Webel AD, Pace RG, Stonebraker JR, Naughton K, Dorfman R, Sandford A, Blackman SM, Berthiaume Y, Pare P, Drumm ML, Zielenski J, Durie P, Cutting GR, Knowles MR, Corey M. A novel lung disease p — View Citation

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 s — View Citation

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. — View Citation

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, Sandfor — View Citation

Zhou YH, Gallins PJ, Pace RG, Dang H, Aksit MA, Blue EE, Buckingham KJ, Collaco JM, Faino AV, Gordon WW, Hetrick KN, Ling H, Liu W, Onchiri FM, Pagel K, Pugh EW, Raraigh KS, Rosenfeld M, Sun Q, Wen J, Li Y, Corvol H, Strug LJ, Bamshad MJ, Blackman SM, Cut — View Citation

Zou F, Lee S, Knowles MR, Wright FA. Quantification of population structure using correlated SNPs by shrinkage principal components. Hum Hered. 2010;70(1):9-22. doi: 10.1159/000288706. Epub 2010 Apr 23. — View Citation

* Note: There are 51 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	This is not an interventional study.	Not applicable. This is not an interventional study.	This is not an interventional study