Bidirectional Mendelian randomization analysis reveals significant associations between Serum DNA repair proteins and...

PurposeThis study investigated causal relationships and underlying mechanisms between serum DNA repair proteins and liver cancer to identify biomarkers for clinical management.MethodsA two-sample bidirectional Mendelian randomization (MR) design was employed. We performed inverse variance weighted (IVW) analysis, followed by protein quantitative trait loci (pQTL), colocalization, and pathway enrichment analyses to explore biological mechanisms.ResultsMR analysis revealed significant associations: NBR1 (IVW: OR = 2.28, 95%CI: 1.17-4.45, P = 0.015) and RAD51 (IVW: OR = 2.16, 95%CI: 1.12-4.15, P = 0.021) were risk factors. PARP11 was protective for hepatocellular carcinoma (OR = 0.48, 95%CI: 0.25-0.93, P = 0.030) but a risk for intrahepatic cholangiocarcinoma (OR = 1.86, 95%CI: 1.04-3.33, P = 0.038). Mechanistically, pQTL and colocalization identified rs2793568 as a key regulator of PARP1, which was enriched in base excision repair pathways. Sensitivity analyses confirmed the robustness of these findings.ConclusionSerum NBR1, RAD51, and PARP11 are potentially causal in liver cancer pathogenesis. Specifically, the genetic regulation of PARP1 highlights a critical DNA repair mechanism, supporting their utility as predictive biomarkers.