Novel telomerase variants in patients with cirrhosis awaiting liver transplantation

Abstract

Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and 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 TERT and TERC have been observed at a higher prevalence in patients with liver disease compared to 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 seventeen patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the RTEL1 gene which 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% CI, ‐7% to ‐46%, p‐value=0.01) compared to 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 one 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. Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer post‐operative length of stay with an IRR of 2.16 (95% CI 1.31, 3.68).

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