Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing (WES) data that might be associated with IND-ALF clinical outcomes.
Bioinformatics analysis was performed on WES data for 22 IND-ALF patients. A two-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared to that in control populations identified. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium (MELD-Na) and Acute Liver Failure Study Group (ALFSG) prognostic scores.
31 SNPs were found associated with a higher relative risk in the IND-ALF population compared to those in controls, of which 11 belong to the HLA class II genes but none for the class I. Further analysis showed that five SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5, rs9272712 of HLA-DQA1, and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using three selected SNPs, a model for polygenic risk score (PRS) was developed to predict IND-ALF prognoses, which are comparable with those by MELD-Na and ALFSG prognostic scores.
Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management.