Potentially functional genetic variants in ferroptosis‐related CREB3 and GALNT14 genes predict survival of hepatitis B virus‐related hepatocellular carcinoma

Abstract Background Ferroptosis is a known crucial player in the development of cancers. However, the effect of single nucleotide polymorphisms (SNPs) in ferroptosis‐related genes on survival in hepatitis B virus (HBV)‐related hepatocellular carcinoma (HBV‐HCC) patients remains unknown. Methods We used two‐stage multivariable Cox proportional hazards regression analyses to estimate the associations between 48,774 SNPs in 480 ferroptosis‐related genes and overall survival (OS) of 866 HBV‐HCC patients. Results We identified that two potentially functional SNPs ( CREB3 rs10814274 C > T and GALNT14 rs17010547 T > C) were significantly independently associated with the OS of HBV‐HCC patients (CT + TT verse CC, hazards ratio (HR) = 0.77, 95% confidence interval (CI) = 0.67–0.89, p < 0.001 for rs10814274 and TC + CC verse TT, HR = 0.66, 95% CI = 0.53–0.82, p < 0.001 for rs17010547, respectively). Additional joint assessment of protective genotypes of these two SNPs showed that patients with 1–2 protective genotypes had a significantly better OS compared with those carrying 0 protective genotypes (HR = 0.56, 95% CI = 0.45–0.70, p < 0.001). Moreover, the expression quantitative trait loci (eQTL) analysis revealed that the survival‐associated SNP rs10814274 T allele was significantly correlated with reduced CREB3 transcript levels in both normal liver tissues and whole blood cells, while the GALNT14 rs17010547 C allele had a significant correlation with increased GALNT14 transcript levels in whole blood cells. Conclusion These results suggest that genetic variants of CREB3 and GALNT14 may affect the survival of HBV‐HCC patients, likely via transcriptional regulation of respective genes. However, further studies are required to confirm these findings.