The impact of transmembrane 6 superfamily 2 (TM6SF2) rs58542926 on liver-related events in patients with advanced chronic liver disease
Lorenz Balcar, Bernhard Scheiner, Markus Urheu, Patrick Weinberger, Rafael Paternostro, Benedikt Simbrunner, Georg Semmler, Claudia Willheim, Matthias Pinter, Péter Ferenci, Michael Trauner, Thomas Reiberger, Albert Friedrich Stättermayer, Mattias Mandorfer
Abstract
Background & aimsGenetic factors such as the transmembrane 6 superfamily 2 (TM6SF2) rs58542926 single nucleotide variant(SNV) modulate the susceptibility for (advanced) chronic liver disease ([A]CLD). However, the impact of this variant in patients who have already progressed to ACLD is unknown.MethodsThe association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement.ResultsMean HVPG was 15±7 mmHg and mean UNOS MELD (2016) 11±5 points. Viral hepatitis (n = 495, 53%) was the most common cause of ACLD, followed by alcohol-related (ARLD; n = 342, 37%) and non-alcoholic fatty liver disease (NAFLD; n = 101, 11%).While 754 (80%) patients harboured the TM6SF2 wild-type (C/C), 174 (19%) and 10 (1%) patients had one or two T-alleles. At baseline, patients with at least one TM6SF2 T-allele had more pronounced portal hypertension (HVPG: 16±7 vs. 15±7 mmHg; p = 0.031), higher gamma-glutamyl transferase levels (123 [63-229] vs. 97 [55-174] UxL−1; p = 0.002), and more commonly hepatocellular carcinoma (17% vs. 12%; p = 0.049).Harbouring the TM6SF2 T-allele was associated with the composite endpoint hepatic decompensation/liver transplantation/liver-related death (SHR: 1.44 [95%CI: 1.14-1.83]; p = 0.003). This was confirmed in multivariable competing risk regression analyses that were adjusted for severity of portal hypertension and hepatic dysfunction at baseline.ConclusionThe TM6SF2 variant modulates liver disease progression beyond the development of ACLD, as it modifies the risks of hepatic decompensation and liver-related death, independently of baseline liver disease severity.