The impact of donor and recipient HSD17B13, PNPLA3 and TM6SF2 genotype on post-transplant fibrosis, steatosis and survival in liver transplant recipients

Introduction The link between certain genetic variants and severity of metabolic dysfunction associated steatotic liver disease (MASLD) is well established. The G-allele in position rs738409 of PNPLA3 and the T-allele in position rs58542926 of TM6SF2 are known to contribute to the development of steatosis, steatohepatitis and fibrosis. The A-allele in position rs72613567 of HSD17B13 is protective. The aim of our study was to evaluate the impact of those genetic variants of recipients and their respective donors on the development of steatosis, fibrosis and survival after liver transplantation (LT).

Material and Methods In this single-center retrospective study, adults who received a liver transplant between 2000 and 2019 and their respective donors were genotyped for PNPLA3, HSD17B13 and TM6SF2 risk variants. Steatosis after transplantation was assessed using MRI, Fibroscan and/or unenhanced computed tomography. FIB4-score was used as longitudinal surrogate marker for fibrosis risk.

Results In our cohort of 435 liver transplant recipients, 34% developed steatosis after transplantation (median follow-up 8 years). The risk alleles of PNPLA3 and TM6SF2 were more common in liver transplant recipients compared to their respective donors (62% vs 43% for PNPLA3, p<0.001; 19% vs. 10% for TM6SF2, p<0.001). In contrast, the protective G-allele in position rs6834314 of HSD17B13 was more frequent in donors than in recipients (47% vs 37%, p=0.006). A combined risk score composed of PNPLA3, TM6SF2 and HSD17B13 showed higher rates of post-transplant steatosis with higher scores without reaching statistical significance. During long-time follow-up, FIB4-scores were sig. lower in patients homozygous for the protective variant in HSD17B13. The presence of a TM6SF2 risk-allele in LT recipients was associated with a sig. shorter median survival (16 years vs 9 years, p<0.001), independent of age, sex and donor TM6SF2 genotype.

Conclusion PNPLA3, TM6SF2 and HSD17B13 variants cause specific risk alterations after liver transplantation.

Publication History

Article published online:
13 May 2025