Genetic variation in oxidative stress and detoxification pathways associated with prostate cancer susceptibility: a pathway-based analysis.

Redox imbalance and impaired detoxification pathways have been implicated in prostate carcinogenesis; however, the specific genetic variants that modulate these processes remain insufficiently characterized. We used a two-stage, pathway-focused design in which PRACTICAL consortium meta-GWAS summary statistics (79,148 cases and 61,106 controls) were used for initial gene-level prioritization, whereas formal variant-level effect estimation was based on FinnGen and UK Biobank summary statistics (19,209 cases and 288,847 controls). PRACTICAL was not included in the formal variant-level meta-analysis because the available data had already been aggregated across multiple contributing studies and were annotated on a different genome build, limiting uniform harmonization and comparability with the two individual biobank datasets. The analysis evaluated 258 variants across 30 genes and prioritized four non-coding candidates: rs3738483 in ARNT, rs4130304 in NFE2L2, rs974334 in GPX6, and rs9606173 in TXNRD2. Three variants met the initial p<0.01 screening threshold; rs9606173 was retained as a borderline candidate (p = 0.011) because it satisfied the remaining allele-frequency, False positive report probability, linkage disequilibrium, functional, pathway-relevance, and assay-feasibility criteria. In the replication cohort (n=560), rs9606173 in TXNRD2 showed nominal associations with prostate cancer (PCa) risk under dominant and overdominant models, although neither association remained significant after Bonferroni correction. Computational annotations and TCGA-PRAD expression analyses supported the biological plausibility of the prioritized genes and variants but did not establish allele-specific function or causality. Overall, this study provides a pathway-based framework for prioritizing biologically plausible PCa susceptibility candidates. These findings should nevertheless be considered exploratory and require replication in larger independent cohorts, together with direct functional validation of the prioritized variants and the redox-regulatory and detoxification pathways highlighted by the analysis.