Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation

Abstract

Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and they are maintained by a ribonucleoprotein complex called telomerase. Variants in genes encoding for telomerase components have been associated with a spectrum of disease in the lung, skin, bone marrow, and liver. Mutations in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a higher prevalence in patients with liver disease compared with the general population; however, the presence of variants in other components of the telomerase complex and their impact on clinical outcomes has not been explored. We evaluated 86 patients with end‐stage liver disease for variants in an expanded panel of eight genes, and found that 17 patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that encodes for a DNA helicase important in telomere maintenance and genomic stability. In gene burden association analysis of their clinical data, the presence of any RTEL1 variant was associated with a 29% lower baseline white blood cell count (95% confidence interval [CI], ‐7% to ‐46%; P Value = 0.01) compared with patients without RTEL1 variants, and the presence of any exonic missense RTEL1 variant was associated with a 42% lower baseline platelet count (95% CI, ‐5% to ‐65%: P Value = 0.03). The presence of any telomerase variant was associated with an increased number of readmissions within 1 year after transplantation demonstrated by an incident rate ratio (IRR) of 3.15 (95% CI, 1.22 to 8.57). No association with survival was observed. Conclusion : Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer postoperative length of stay with an IRR of 2.16 (95% CI, 1.31 to 3.68).

<p>KIAA1522 Promotes the Progression of Hepatocellular Carcinoma via the Activation of the Wnt/β-Catenin Signaling Pathway</p>

“…[4][5][6] Although surgical resection and liver transplantation have been developed to treat HCC, postoperative survival of HCC patients is still not ideal due to high recurrence and rate of metastasis of HCC. [7][8][9] Therefore, there is an urgent need to understand the mechanisms underlying the initiation and development of HCC.…”

Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders

“…In a population of patients with liver cirrhosis awaiting liver transplantation, P/LP TBD gene variants were more prevalent than in the general population and were found to be associated with lower baseline platelet and WBC counts and a longer post-transplant length of stay. [20] To our knowledge, we here present the largest study of liver disease in a cohort of young patients with DC/TBD to date. A strength of our study is that we followed patients over several years (median period of 6 (1.4-8.2) years), thus were able to evaluate liver disease progression over time.…”

“…[13] Another study that included patients with end-stage liver disease awaiting liver transplantation identified heterozygous P/LP variants in RTEL1, TERT, TINF2, or NHP2 in 18 (20%) of the 86 patients studied. [20] The aim of our present study is to characterize baseline hepatic abnormalities in a uniformly evaluated cohort of patients with DC/TBD, examine the trends in relation to the genetic background, and characterize the risk factors associated with liver disease progression.…”

Liver Transplantation for Decompensated Cirrhosis Secondary to Telomerase Reverse Transcriptase Mutation

“…Telomere variants (independent of syndromes) have been associated with post-LT outcomes, suggesting biologic principals outlined may be more broadly applicable. (6) In conclusion, LT for decompensated cirrhosis due to telomere disease is safe and efficacious though requires unique considerations for post-LT care.…”