Constitutional Telomerase Mutations Are Genetic Risk Factors for Cirrhosis

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Hepatology (Impact Factor: 11.06). 05/2011; 53(5):1600-7. DOI: 10.1002/hep.24173
Source: PubMed


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.

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    • "Telomere biology is an emerging field that holds great promise for advancing clinical medicine, particularly for aging and age-related diseases. Short telomeres have been associated with the gamut of age-related diseases, including diabetes mellitus [10, 11], cardiovascular disease [12], liver disorders [13, 14], cancer [15–19], and death from all causes [20]. Moreover, long telomeres have been associated with exceptional longevity and increased lifespan [21]. "
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    • "Accelerated shortening of telomeres associated with a lack of telomerase activity and high cell turnover during chronic hepatitis has been recognized as a hallmark of cirrhosis several years ago [16], [21], [51]. More recently, constitutional “loss-of-function” type of telomerase (TERT or TERC genes) mutations have been identified as a risk factor for cirrhosis [52], [53]. In contrast to cirrhosis, HCC is known to reactivate TERT expression [54], display high telomerase activity [24] and stabilize telomeres [24], [55]. "
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