Genetic Modifiers of Cystic Fibrosis (CF) Liver Disease

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 DeltaF508 (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.

Inclusion Criteria:

- Volunteers with CF, regardless of genotype and age, who have "severe" liver disease
with portal hypertension (big spleen, i.e. "splenomegaly" and/or presence of enlarged
vessels in the esophagus, i.e. esophageal varices) may be eligible to participate.
This would include any person who has been evaluated for a liver transplant, or has
already received a liver transplant.

Exclusion Criteria:

- History of Alcohol Abuse

- History of Biliary Atresia

- History of Clinically Significant Hepatitis Infection

- History of Hepatic Vein Thrombosis

- History of Liver Cancer

- History of Portal Vein Thrombosis

- History of Clinically Significant use of total parenteral nutrition (TPN)

- History of Wilson's Disease