Constitutional telomerase mutations are genetic risk factors for cirrhosis

Rodrigo T. Calado, Jennifer Brudno, Paulomi Mehta, Joseph J. Kovacs, Colin Wu, Marco A. Zago, Stephen J. Chanock, Thomas D Boyer, Neal S. Young

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1600-1607
Number of pages8
JournalHepatology
Volume53
Issue number5
DOIs
StatePublished - May 2011

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Telomerase
Fibrosis
Mutation
Telomere
Genes
Leukocytes
Dyskeratosis Congenita
Germ-Line Mutation
Pulmonary Fibrosis
Gene Frequency
Transfection
Liver Diseases
Healthy Volunteers
Cell Line
Polymerase Chain Reaction
Liver

ASJC Scopus subject areas

  • Hepatology

Cite this

Calado, R. T., Brudno, J., Mehta, P., Kovacs, J. J., Wu, C., Zago, M. A., ... Young, N. S. (2011). Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology, 53(5), 1600-1607. https://doi.org/10.1002/hep.24173

Constitutional telomerase mutations are genetic risk factors for cirrhosis. / Calado, Rodrigo T.; Brudno, Jennifer; Mehta, Paulomi; Kovacs, Joseph J.; Wu, Colin; Zago, Marco A.; Chanock, Stephen J.; Boyer, Thomas D; Young, Neal S.

In: Hepatology, Vol. 53, No. 5, 05.2011, p. 1600-1607.

Research output: Contribution to journalArticle

Calado, RT, Brudno, J, Mehta, P, Kovacs, JJ, Wu, C, Zago, MA, Chanock, SJ, Boyer, TD & Young, NS 2011, 'Constitutional telomerase mutations are genetic risk factors for cirrhosis', Hepatology, vol. 53, no. 5, pp. 1600-1607. https://doi.org/10.1002/hep.24173
Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology. 2011 May;53(5):1600-1607. https://doi.org/10.1002/hep.24173
Calado, Rodrigo T. ; Brudno, Jennifer ; Mehta, Paulomi ; Kovacs, Joseph J. ; Wu, Colin ; Zago, Marco A. ; Chanock, Stephen J. ; Boyer, Thomas D ; Young, Neal S. / Constitutional telomerase mutations are genetic risk factors for cirrhosis. In: Hepatology. 2011 ; Vol. 53, No. 5. pp. 1600-1607.
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AB - 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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