Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease
This study examines "modifier genes" that may play a role in the development of CF liver disease. Modifier genes are genes, other than the CF gene (CFTR), which may directly or indirectly have an affect on how the body responds to the conditions that develop as the result of the defective CFTR gene. Scientists have wondered why some patients with CF develop CF liver disease and why some patients with CF do not. To better understand the problem, this study was designed to examine the genetic makeup of CF patients who are considered to have severe liver disease to see if they can identify any modifier genes. Researchers will study blood samples, pulmonary function tests, and other medical information in hopes that a connection can be made between genetic make-up and how severe the liver disease is. The identification of modifier genes that influence disease severity may ultimately lead to a better understanding of CF liver disease, and may be useful in the development of new treatments.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Genetic Modifiers of CF Liver Disease|
A one time blood draw of 35 mls
|Study Start Date:||March 2004|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||July 2015 (Final data collection date for primary outcome measure)|
The clinical heterogeneity in cystic fibrosis (CF) is only partly explained by mutations in the CFTR gene. Most CF patients have evidence of liver dysfunction and focal biliary cirrhosis (fibrosis), and a subset of these patients (5-7%) progresses to severe liver disease (CFLD), as defined by portal hypertension and multilobular cirrhosis. The development of CFLD has no relationship to specific CFTR mutations or other biomarkers, and there is currently no way to identify which CF infants will develop severe liver disease.
The central hypothesis of this proposal is that the development of CFLD reflects the influence of non-CFTR "modifier" alleles (genes). This project is designed to identify associations between non-CFTR genes and CFLD, and test the biological effect of selected alleles on hepatic fibrosis in transgenic murine models. We hypothesize that polymorphisms in multiple genes, each with a conceptual or mechanistic link to liver disease, increase the risk for developing end-stage CF liver disease, and that interactions among these risk factors will define the pathophysiology of this disorder. To achieve our goals, we will study 400 CF patients with well-documented severe liver disease and portal hypertension, and 400 gender and genotype-matched CF patients > age 15 years who have no evidence of CFLD. We propose to identify heritable risk factors for the development of CFLD by evaluation of functional sequence variants within, and single nucleotide polymorphisms associated with, multiple genes associated with CFLD pathogenesis. To test ("validate") the biological effects (impact) of selected genetic alleles on liver fibrosis, we will develop transgenic mice homozygous for DF508, who are also expressing an additional candidate gene modifier allele. Better definition of the complex genotypes that increase risk for severe liver disease in CF will allow early identification of CF infants predisposed to develop end-stage liver disease, and thereby allow testing of currently available therapies. Better understanding of the pathobiology of hepatic fibrosis in CF will identify novel targets to prevent (or reduce) the development of CFLD.
|Contact: Michael R Knowles, MDfirstname.lastname@example.org|
|Contact: Beth Godwin, BAemail@example.com|
|United States, North Carolina|
|The University of North Carolina at Chapel Hill||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Michael R Knowles, MD 919-966-6780 firstname.lastname@example.org|
|Contact: Beth Godwin, BA 919-966-6780 email@example.com|
|Principal Investigator:||Michael R Knowles, MD||University of North Carolina, Chapel Hill|