Genetic Variants of GBP4: Reduced Risks for Drug‐Induced Acute Liver Failure in Non‐Finnish European Population

• Published in: Liver international 2025-02, Vol.45 (2), p.e70011-n/a
• Main Authors: Liao, Tsung‐Jen, Xia, Menghang, Hayashi, Paul, Pan, Bohun, Aithal, Guruprasad P., Lucena, M. Isabel, Andrade, Raúl J., Rule, Jody A., Lee, William M., Rakela, Jorge, Huang, Ruili, Chen, Minjun
• Format: Article
• Language: English
• Subjects: Adult; Aged; Case-Control Studies; Chemical and Drug Induced Liver Injury - genetics; drug‐induced acute liver failure; Exome Sequencing; Female; GBP4; Gene frequency; Gene sequencing; Genetic analysis; Genetic diversity; Genetic Predisposition to Disease; genetic risk factor; Genetic variance; Genotypes; GTP-Binding Proteins - genetics; Humans; IFN‐γ signalling; Innate immunity; Liver; Liver diseases; Liver Failure, Acute - chemically induced; Liver Failure, Acute - genetics; Male; Middle Aged; Phenotypes; Phenotypic variations; Pilot Projects; Polymorphism, Single Nucleotide; Population genetics; Population studies; Proteins; Replication; Variance analysis; White People - genetics; Whole genome sequencing
• ISSN: 1478-3223; 1478-3231; 1478-3231
• DOI: 10.1111/liv.70011

ABSTRACT Background and Aims Acute liver failure (ALF) is a serious condition, typically in individuals without prior liver disease. Drug‐induced ALF (DIALF) constitutes a major portion of ALF cases. Our research aimed to identify potential genetic predispositions to DIALF. Methods We analysed the potential genetic variants associated with DIALF using the whole exome sequencing data from 75 cases, including 40 non‐Finnish European cases in the pilot study. Chi‐square tests were performed for case–control analysis against the 1000 genomes project as the control. A replication study of 44 DIALF cases that included 24 non‐Finnish Europeans was conducted to validate candidate variants. The association between clinical phenotype and genotypes was analysed using one‐way analysis of variance. Results Eight variants (rs561037, rs561042, rs608339, rs655260, rs1142886, rs1142888, rs1142889 and rs1142890) in the guanylate binding protein 4 (GBP4) were significantly associated with DIALF in non‐Finnish Europeans in the pilot study and confirmed in the replication study. Rs561037 and rs561042 were highly significant with the lowest allele frequencies in both pilot and replication studies. An association was also found between these variants and milder clinical outcomes, indicated by lower peak levels of ALT, AST and higher Karnofsky performance scores. Conclusion Our study identified eight GBP4 missense variants linked to a lower risk of DIALF in the non‐Finnish European population. The GBP4 protein, activated by interferon‐gamma, plays a critical role in innate immunity. These findings suggest that GBP4 variants might influence immune and inflammatory responses in DIALF, though further studies are needed to elucidate the underlying mechanisms.