The PNPLA3 rs738409 GG genotype is associated with poorer prognosis in 239 patients with autoimmune hepatitis

Background: Fibrosis progression in autoimmune hepatitis can be attenuated by immunosuppressive treatment; however, some patients progress despite therapy. Single nucleotide polymorphisms (SNPs) such as PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 are associated with non-alcoholic fatty liver disease and fibrosis progression, whereas a splice variant in HSD17B13-rs72613567:TA has been shown to be protective. Aim: To analyse the impact of different SNPs on the long-term outcome of patients with autoimmune hepatitis. Methods: We included 239 patients into this study who had been treated between 1983 and 2018 for autoimmune hepatitis. Genomic DNA was isolated from whole blood and SNPs were determined by PCR analysis. Liver biopsies were available for 215/239 patients (90%). Clinical and laboratory patient data were assessed by chart review. Results: Mean age at baseline was 42.1 years with 74.1% being female. The median follow-up was 9.4 years (IQR 3.5-15.0), 11.7% of the patients (n = 28) died or required liver transplantation. In the Kaplan-Meier analysis of the combined endpoint time to liver transplantation or death, we observed that patients with the PNPLA3-rs738409 GG variant met more frequently the primary endpoint (P = 0.005). In Cox regression analysis PNPLA3-rs738409 GG as well as liver cirrhosis were identified as strong predictors for time to liver transplantation or death (HR 4.5 [CI 1.48-13.72], P = 0.008 and HR 9.24 [CI 2.11-40.44], P = 0.003, respectively). Neither steatosis, diabetes mellitus nor obesity were associated with outcome. Conclusions: PNPLA3-rs738409 variant GG is a predictor for time to liver transplantation or death and may help to identify autoimmune hepatitis patients at risk for disease progression.