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

Abstract

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. The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement. Mean 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. 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.