m6A-SNPs identified by integrating genomic data are associated with the occurrence and prognosis of HCC.

N6-methyladenosine (m6A), a prevalent mRNA modification, plays a key role in cancer. m6A-associated single nucleotide polymorphisms (m6A-SNPs) have been implicated in various diseases, but their role in Hepatocellular Carcinoma (HCC) is unclear. This study aimed to identify HCC-related m6A-SNPs and validate their clinical relevance. We integrated HCC genome-wide association study (GWAS) data with the RMVar database to screen for candidate m6A-SNPs, which were further prioritized by expression quantitative trait locus (eQTL) and differential gene expression analyses. Final validation was performed in a case-control cohort comprising 800 HCC patients and 800 matched controls from a northern Chinese population. In silico analysis identified 331 HCC-related m6A-SNPs, 176 of which exhibited eQTL signals. Among them, 19 SNPs corresponded to 19 genes that showed differential expression in at least one public dataset. Further case-control study showed that 12 of these 19 SNPs were significantly associated with HCC risk or clinical progression. Notably, after false discovery rate (FDR) correction, rs7947978 was associated with an increased risk of overall and HBV-related HCC, rs61560753 was associated with tumor number, and rs9875668 and rs3847607 were linked to clinical liver function parameters (rs9875668 with AST, ALT and AST/ALT ratio; rs3847608 with AST). This comprehensive analysis indicates that specific m6A-SNPs are implicated in HCC susceptibility and progression, highlighting their potential as biomarkers for risk prediction and therapeutic targeting.