Advertisement

Topics

Gene Modifiers of Cystic Fibrosis Lung Disease

2014-08-27 03:56:05 | BioPortfolio

Summary

Ths 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.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Conditions

Cystic Fibrosis

Location

CTRC
Chapel Hill
North Carolina
United States
27599-7600

Status

Recruiting

Source

National Heart, Lung, and Blood Institute (NHLBI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:56:05-0400

Clinical Trials [886 Associated Clinical Trials listed on BioPortfolio]

Miglustat / OGT 918 in the Treatment of Cystic Fibrosis

Cystic fibrosis is a genetic disease caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of the study is to investigate the effects of miglust...

Exercise-Induced Bronchospasm in Cystic Fibrosis

Exercise is an important clinical feature in cystic fibrosis. Better exercise capacity has been associated with better patient outcomes and quality of life. Exercise-induced bronchospasm...

Phase I Study of Liposome-Mediated Gene Transfer in Patients With Cystic Fibrosis

OBJECTIVES: Evaluate the efficacy and safety of lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator gene to nasal epithelium in patients with cystic f...

Study of Uridine Triphosphate (UTP) as an Aerosol Spray for Cystic Fibrosis

OBJECTIVES: I. Determine the stability of uridine triphosphate (UTP) and examine the metabolism of exogenous nucleotides on airway epithelial surfaces in patients with cystic fibrosis. ...

Determination of the Predictive Factors in the Reversibility or the Aggravation in the Disorders of the Glucose Metabolism in Cystic Fibrosis Patients

For some years, the investigators observe an increase of the arisen of diabetes in cystic fibrosis patients However, this diabetes may be reversible. The investigators speak about " Cystic...

PubMed Articles [1721 Associated PubMed Articles listed on BioPortfolio]

Lack of efficacy of Lactobacillus GG in reducing pulmonary exacerbations and hospital admissions in children with cystic fibrosis: A randomised placebo controlled trial.

Intestinal dysbiosis has been described in Cystic Fibrosis (CF) and probiotics have been proposed to restore microbial composition. Aim of the study was to investigate the effects of Lactobacillus rha...

End-of-life practice patterns at U.S. adult cystic fibrosis care centers: A national retrospective chart review.

There are many challenges to providing end-of-life care (EOLC) to people with cystic fibrosis (CF).

Audiometric assessment of pediatric patients with cystic fibrosis.

The purpose of this study was to evaluate hearing impairment in pediatric patients with cystic fibrosis (CF).

The association between Staphylococcus aureus and subsequent bronchiectasis in children with cystic fibrosis.

Staphylococcus aureus (S. aureus) may be related to more rapid progression of cystic fibrosis (CF) lung disease.

Fecal calprotectin concentrations in young children with cystic fibrosis: Authors response.

Medical and Biotech [MESH] Definitions

An autosomal recessive genetic disease of the EXOCRINE GLANDS. It is caused by mutations in the gene encoding the CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR expressed in several organs including the LUNG, the PANCREAS, the BILIARY SYSTEM, and the SWEAT GLANDS. Cystic fibrosis is characterized by epithelial secretory dysfunction associated with ductal obstruction resulting in AIRWAY OBSTRUCTION; chronic RESPIRATORY INFECTIONS; PANCREATIC INSUFFICIENCY; maldigestion; salt depletion; and HEAT PROSTRATION.

A chloride channel that regulates secretion in many exocrine tissues. Abnormalities in the CFTR gene have been shown to cause cystic fibrosis. (Hum Genet 1994;93(4):364-8)

A strain of mice widely studied as a model for cystic fibrosis. These mice are generated from embryonic stem cells in which the CFTR (cystic fibrosis transmembrane conductance regulator) gene is inactivated by gene targeting. As a result, all mice have one copy of this altered gene in all their tissues. Mice homozygous for the disrupted gene exhibit many features common to young cystic fibrosis patients, including failure to thrive, meconium ileus, and alteration of mucous and serous glands.

A species of STENOTROPHOMONAS, formerly called Xanthomonas maltophilia, which reduces nitrate. It is a cause of hospital-acquired ocular and lung infections, especially in those patients with cystic fibrosis and those who are immunosuppressed.

A rehabilitation therapy for removal of copious mucus secretion from the lung of patients with diseases such as CHRONIC BRONCHITIS; BRONCHIECTASIS; PULMONARY ABSCESS; or CYSTIC FIBROSIS. The patient's head is placed in a downward incline (so the TRACHEA is inferior to the affected area) for 15- to 20-minute sessions.

More From BioPortfolio on "Gene Modifiers of Cystic Fibrosis Lung Disease"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topic

Pulmonary
Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza,  Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...


Searches Linking to this Trial