Constitutional telomerase mutations are genetic risk factors for cirrhosis

Authors

  • Rodrigo T. Calado,

    Corresponding author
    1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
    • Hematology Branch,National Heart, Lung, and Blood Institute, Bethesda, MD
    Search for more papers by this author
  • Jennifer Brudno,

    1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
    2. Clinical Research Training Program; National Institutes of Health, Bethesda, MD
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Paulomi Mehta,

    1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
    2. Clinical Research Training Program; National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Joseph J. Kovacs,

    1. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Colin Wu,

    1. Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD
    Search for more papers by this author
  • Marco A. Zago,

    1. Division of Hematology, Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil
    Search for more papers by this author
  • Stephen J. Chanock,

    1. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author
  • Thomas D. Boyer,

    1. Liver Research Institute, University of Arizona School of Medicine, Tucson, AZ
    Search for more papers by this author
  • Neal S. Young

    1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
    Search for more papers by this author

  • Supported by the National Institutes of Health (NIH) Intramural Research Program. J.B. and P.M.'s research years were made possible through the Clinical Research Training Program (CRTP), a public-private partnership supported jointly by the NIH and Pfizer (grant to the Foundation for NIH from Pfizer).

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. (HEPATOLOGY 2011;)

Ancillary