An international scientific collaboration has resulted in the discovery of the first genetic risk factor for severe liver disease development in some people with cystic fibrosis (CF). CF is an inherited disease that affects mainly the lungs, pancreas, and sweat glands. However, many individuals with CF also develop abnormal liver function and fibrosis, with a some progressing to severe liver disease. The major genetic defects responsible for CF are known to be mutations in the gene called CFTR, which result in mucus accumulation in airways and abnormal function of other organs. However, the process by which liver disease develops in individuals with CF is unclear, and patients with the mutated CFTR gene exhibit a wide range of disease severity. Based on these observations, additional genetic factors likely play a role in determining susceptibility to liver disease development in patients with CF. Currently, no diagnostic test exists to identify which individuals with CF are at high-risk of developing severe liver disease.
In order to study a sufficiently large number of individuals with CF, researchers at sites around the globe worked together to identify genetic risk factors associated with severe liver disease development in CF. They increased their chances of finding these genetic factors by performing two sequential studies of patients with CF and healthy controls: an initial study examining five genes suspected of contributing to CF liver disease, followed by a second study to confirm these genetic associations. In the initial study, two genetic variants, one in the SERPINA1 gene, referred to as the SERPINA1 Z allele, and another in the TGFB1 gene, were associated with CF liver disease; however, the second study confirmed only SERPINA1 Z allele as a risk factor. When the data from both studies were combined for greater statistical power, the SERPINA1 Z allele was shown to have a strong association with CF liver disease. The SERPINA1 Z allele is known to cause proteins to fold incorrectly and to accumulate in liver cells; however the mechanism by which it contributes to CF liver disease requires further study.
This research identifies the SERPINA1 Z allele as the first genetic factor that increases the risk of developing severe liver disease in individuals with CF. This discovery allows for the possibility of future infant screening programs that follow up on diagnosis of CF by testing for their genetic susceptibility to develop severe liver disease later in life, so that appropriate preemptive action can be taken.
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Bartlett JR, et al. for the Gene Modifier Study Group: Genetic Modifiers of Liver Disease in Cystic Fibrosis. JAMA 302: 1076-1083, 2009.
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