Some patients with
liver disease progress to
cirrhosis, but the risk factors for
cirrhosis development are unknown.
Dyskeratosis congenita, an
inherited bone marrow failure syndrome associated with mucocutaneous anomalies,
pulmonary fibrosis, and
cirrhosis, is caused by germline mutations of genes in the
telomerase complex. We examined whether
telomerase mutations also occurred in sporadic
cirrhosis. In all, 134 patients with
cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and
TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into
telomerase-deficient cell lines, and
telomerase activity was measured in cell lysates. Nine of the 134 patients with
cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with
cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a
TERC mutation. The mean telomere length of leukocytes in patients with
cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004).
CONCLUSION: Most TERT gene variants reduced
telomerase enzymatic activity in vitro. Loss-of-function
telomerase gene variants associated with short telomeres are risk factors for sporadic
cirrhosis.