The impact of transmembrane 6 superfamily 2 (TM6SF2) rs58542926 on liver-related events in patients with advanced chronic liver disease

Background & aims: Genetic 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. Methods: The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement. Results: Mean HVPG was 15 & PLUSMN;7 mmHg and mean UNOS MELD (2016) 11 & PLUSMN;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 & PLUSMN;7 vs. 15 & PLUSMN;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. Conclusion: The 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. & COPY; 2023 The Authors. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )