It is possible that telomerase mutations would impair the regenerative reserves of hepatocytes in the context of chronic liver damage. Accordingly, an increased frequency of telomerase mutations could be associated with cirrhosis induced by chronic liver diseases. Here, we sequenced the TERT and TERC genes in a cohort of 1,121 individuals, 521 patients with liver cirrhosis and 600 controls. The analysis revealed a significantly increased frequency of telomerase mutations in cirrhosis patients (14 heterozygous, two homozygous allelic variants in 521 individuals; allele frequency 0.017) compared to controls (three heterozygous sequencing

variants in 600 individuals; 0.003, P value 0.0007; Relative risk [RR] 1.859; 95% confidence interval [CI] 1.552-2.227). Cirrhosis-associated telomerase Everolimus price mutations showed functional defects and were associated with the evolution of disease complications. Together, these data provide the first demonstration of a broad involvement of telomerase mutations in the evolution and Pirfenidone cell line progression of cirrhosis in response to chronic liver injury. The finding could impact on the future development of molecular therapies and surveillance programs in patient with chronic liver disease. DKC, dyskeratosis congenita; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PCR, polymerase

chain reaction; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TRAP, telomere repeat amplification protocol; TRF telomere restriction fragment. A total of 1,121 individuals were recruited for the current study. Among them, 521 patients were diagnosed MCE with liver cirrhosis; 600 controls were either healthy individuals (n = 473) or patients with chronic HCV infection

who did not develop cirrhosis during follow-up (average time of follow-up: 21 years, n = 127). We included the group of hepatitis C carriers who did not progress towards liver cirrhosis because this cohort provides an important control indicating that telomerase mutations do associate with the development of cirrhosis and not with the occurrence of chronic liver disease per se. Subjects were recruited from (1) the Liver Unit, Hôpital Jean Verdier in Bondy Cedex, France, (2) the Department of Gastroenterology, Hepatology and Endocrinology of Hannover Medical School in Hannover, Germany, (3) the Henriettenstiftung Hannover, Germany, (4) the Institute for Clinical Transfusion Medicine and Immunogenetics, DRK Blood Donor Service Baden-Württemberg-Hesse, University of Ulm, and (5) the Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. The study was approved by the local Institutional Review Boards and written informed consent was obtained from all subjects. The study was designed in accordance with the principles of the Declaration of Helsinki and patient data were evaluated anonymously.