The total allele frequency of telomerase mutations in cirrhosis patients was 0.017, compared to 0.003 in healthy controls or hepatitis C patients without fibrosis progression (P = 0.0007). Furthermore, subgroup analysis (number of identified mutations in healthy controls compared to

the cirrhosis group: P = 0.0021, number of mutations in chronic liver disease patients without cirrhosis compared to the cirrhosis group: P = 0.0349) Cilomilast cost reconfirmed that the identified telomerase mutations are associated with cirrhosis but do not occur in healthy controls or patients with indolent HCV infection. To our knowledge, these data

represent the first association of telomerase mutations with the evolution and progression of cirrhosis in response to chronic liver injury. The ethnic group in our study consisted mainly of whites (70.1%). It remains to be analyzed whether telomerase mutations occur with similar frequency in other ethnic groups. The study shows that ACP-196 cell line cirrhosis-associated TERT mutations exhibit an impaired function compared to wildtype TERT. Cirrhosis-associated telomerase mutations result in reduced telomerase activity, impaired telomere maintenance, and reduced growth rates of fibroblasts and lymphocytes. Moreover,

a reduction in telomere length was seen in peripheral blood and immortalized lymphocytes of mutation carriers compared to controls. We did not see any significant difference in the percentage of γH2Ax-positive hepatocytes between liver cirrhosis patients with and without telomerase mutations. This, however, does not argue against an involvement of telomerase mutations in cirrhosis. Previous studies have demonstrated that telomere shortening and senescence are general signs of cirrhosis induced by different etiologies.13, 14 We propose that telomerase mutations can lead to accelerated telomere shortening, thus shortening the time to progression of chronic liver disease toward Cyclooxygenase (COX) cirrhosis. In addition, telomerase mutations may have extratelomeric effects influencing disease progression. Recent studies have revealed telomere length-independent effects of TERT in regulating the transcriptional function of the Wnt-signaling pathway and stem cell activity in mice.32 It remains to be seen whether cirrhosis-associated TERT mutations show defects in these noncanonical TERT-pathways and whether TERT mutations affect the latency of cirrhosis development in patients with chronic liver disease.