Genetic Risk Factor for Liver Disease for Patients With Cystic Fibrosis

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A genetic analysis indicates that a certain gene variation in patients with cystic fibrosis may significantly increase their risk of developing severe liver disease, according to a study in the September 9 issue of JAMA.

A small fraction (about 3% to 5%) of patients with cystic fibrosis develop severe liver disease characterized by cirrhosis with portal hypertension (CFLD). Previous research has suggested that genetic variability that is not associated with the cystic fibrosis transmembrane conductance regulator (CFTR) gene may contribute to the risk for severe liver disease.

Jaclyn R. Bartlett, PhD, of the University of North Carolina at Chapel Hill, and colleagues examined 9 variants in 5 genes previously studied in CFLD to determine the association between non-CFTR genetic variations and CFLD. The initial study compared genetic variations in candidate genes in persons with CFLD (n = 124) and in control patients without CFLD (n = 843), with a second study testing these findings in different populations of patients with (n = 136) and without (n = 1,088) CFLD.

This international collaboration compiled the largest number of samples ever from cystic fibrosis patients with severe liver disease.

The researchers found that of the 5 genes studied, “only the SERPINA1 Z allele was significantly associated with CFLD and portal hypertension. This polymorphism is relatively uncommon in CF [about 2.2 percent of patients with CF are carriers], but the odds ratio for association with severe liver disease is relatively high [about 5 times higher] for the contribution of a genetic modifier to a mendelian disorder…. Moreover, the estimated population-attributable risk among patients with CF is 6.7 percent. From a clinical perspective, a rare variant with large penetrance (such as the Z allele) may be more useful than a common variant with low penetrance in screening for genetic polymorphisms,” the researchers note.

“The identification of the SERPINA1 Z allele as the first marker for the development of severe liver disease in CF illustrates the possibility of identifying CF risk factors early in life, conceptually as a secondary component of neonatal screening after the diagnosis of CF is confirmed,” the authors conclude.

For more details, see “Genetic modifiers of liver disease in cystic fibrosis,” JAMA 2009;302:1076–1083.