Telomerase mutation: A genetic risk factor for cirrhosis

T he pathogenesis of liver cirrhosis is a complex process for which the mechanisms are not completely elucidated. Although exogenous or environmental risk factors leading to chronic liver injury, such as viral hepatitis B and C infection, alcohol intake, or fatty liver disease, can be identified in most patients with cirrhosis, approximately 5% of patients with cirrhosis have no apparent risk factors. In addition, patients with identical risk factors have a diverse spectrum of clinical manifestations. The reasons why some patients with identifiable risk factors progress to cirrhosis whereas others have a benign course remain unclear and cannot be completely explained by known environmental and/or obvious host factors (i.e., age and sex). Therefore, a genetic predisposition may contribute to the development of cirrhosis. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the last decade. Data from epidemiologic studies reported the prevalence of cryptogenic cirrhosis as 3.1-fold higher in Hispanic Americans, but 3.9-fold lower in African Americans than in European Americans despite the same prevalence of diabetes in Hispanics and African Americans. Studies of the National Academy of Sciences–National Research Council Twin Registry reported that concordance rates for developing alcoholic cirrhosis were significantly higher in monozygotic twins than in dizygotic twins (16.9% versus 5.3%, P < 0.001). Recently, Huang et al. proposed a cirrhosis risk score based on a genetic marker panel (seven single-nucleotide polymorphisms [SNPs] in six genes: AP3S2 [adaptor-related protein complex 3, sigma 2 subunit], AQP2 [aquaporin 2], AZIN1 [antizyme inhibitor 1], STXBP5L [syntaxin binding protein 5-like], TLR4 [Toll-like receptor 4], and TRPM5 [transient receptor potential cation channel, subfamily M, member 5, and in the intergenic region between DEGS1 [degenerative spermatocyte homolog 1], NVL [nuclear valosin-containing protein-like]) for identifying the risk of developing cirrhosis in Caucasian patients with chronic hepatitis C infection. This score had a higher area under the receiver operating characteristics curve compared to clinical factors (age, sex, alcohol) (0.73 versus 0.53) and has been validated in another group of Caucasian patients with mild chronic hepatitis C infection (METAVIR stage F0-F2 at initial liver biopsy). Furthermore, the association of an SNP in the PNPLA3 (patatin-like phospholipase domain-containing protein 3) gene (rs738409) with fibrosis in patients with nonalcoholic steatohepatitis and with alcoholic cirrhosis has also been reported. These data suggest that genetic risk factors influence the progression to cirrhosis. The functional bases for the predispositions due to these SNPs have not been completely characterized. In addition to the results from SNP studies, the concept of telomere shortening as a genetic risk factor for cirrhosis has been proposed. Telomeres consist of repeat DNA sequences (TTAGGG) and a specialized protein complex named the telosome or shelterin. They are located at the ends of linear chromosomes, the so-called ‘‘tips of the chromosomes’’, and function as a ‘‘cap’’ to protect the chromosome from end-to-end fusion and destruction by nuclease and/or ligase enzymes. Telomerase is an enzymatic protein complex, comprising two essential components: telomerase reverse transcriptase (hTERT) and a telomerase RNA component (hTERC). This enzymatic complex is responsible for maintaining telomere length by synthesizing new DNA sequences and adding them to the end of the chromosome. Nevertheless, during each cell division, telomere length inevitably reduces due to the inability of DNA polymerase to fully replicate the terminal chromosomal segment. Once telomeres are critically short, a DNAdamage program is activated that leads either to apoptosis or cell senescence. Because continuous DNA turnover accelerates telomere shortening, this process is accentuated in conditions with high cell turnover such as chronic liver injury. The resulting cellular growth arrest and/or senescence appears to be profibrogenic by as-yet undefined mechanisms. Kitada et al. were the first to demonstrate the relationship between telomere shortening and cirrhosis in 1995. Telomere length in tissue from cirrhotic liver Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SNP, single-nucleotide polymorphism; TERT, telomerase reverse transcriptase; TERC, telomerase RNA component. Address reprint requests to: Lewis R. Roberts, M.B. CH.B. , Ph.D., Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: roberts.lewis@mayo.edu; fax: 507-284-0762. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24304 Potential conflict of interest: Nothing to report.