Potentially functional variants of CYP2A6 and ABHD12 in the arachidonic acid metabolism pathway genes predict the survival of HBV-related hepatocellular carcinoma patients

Arachidonic acid (AA) metabolism plays essential roles in inflammation, tissue regeneration, immune regulation, and tumorigenesis. However, the prognostic significance of genetic variants in AA metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. We analyzed 56 AA metabolism-related genes in 866 HBV-HCC patients using Cox proportional hazards regression, with Bayesian false discovery probability and false positive report probability for multiple testing correction. Two independent SNPs, CYP2A6 rs28399433 A > C (HR = 1.30, 95% CI = 1.07–1.58, P = 0.008) and ABHD12 rs3827014 C > T (HR = 0.69, 95% CI = 0.52–0.93, P = 0.013), were identified. A genetic score combining protective alleles showed a dose-dependent association with improved overall survival (Ptrend<0.001), with significant multiplicative interactions with smoking (Pinteraction=0.016) and alcohol consumption (Pinteraction=0.049), and additive interactions for smoking (RERI = 0.65, 95% CI = 0.10–1.19) and BCLC stage B/C (RERI = 1.25, 95% CI = 0.17–2.33). Functional validation with luciferase reporter assays demonstrated allele-specific effects on gene expression (P < 0.001). Lower CYP2A6 and higher ABHD12 levels in HCC tissues compared to normal were observed in the UALCAN database (P = 6.43 × 10⁻⁷ for CYP2A6; P < 1.00 × 10⁻¹² for ABHD12) and in 103 paired tumor/normal tissues. Survival analysis using the KMplot database indicated that decreased CYP2A6 and increased ABHD12 expression were associated with poorer survival (P < 0.001 and P = 0.008, respectively). These findings suggest that functional variants in CYP2A6 and ABHD12 may serve as novel survival biomarkers for HBV-HCC by regulating gene expression.