Ignite Creation Date:
2024-05-05 @ 11:25 AM
Last Modification Date:
2024-10-26 @ 9:07 AM
Study NCT ID:
NCT00037765
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-12-06
First Post:
2002-05-20
Brief Title:
Gene Modifiers of Cystic Fibrosis Lung Disease
Sponsor:
University of North Carolina Chapel Hill
Organization:
University of North Carolina Chapel Hill
Study Overview
Official Title:
Gene Modifiers of Cystic Fibrosis Lung Disease
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to examine genetic modifiers of the severity of cystic fibrosis lung disease
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 phenotypegenotype 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 13 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 ie homozygous deltaF508 and who are at the extremes of pulmonary phenotype ie 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 n200 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
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 phenotypegenotype 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 13 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 ie homozygous deltaF508 and who are at the extremes of pulmonary phenotype ie 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 n200 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 5R01HL068890 | NIH | None | httpsreporternihgovquickSearch5R01HL068890 |