Whole-blood total chromium and DNA repair variation in an occupational Cr(VI)-exposure setting: Pathway-resolved associations across complementary response biomarkers

Biological responses vary among workers in occupational hexavalent chromium [Cr(VI)]-exposure settings, but evidence for DNA-repair susceptibility is complicated by extensive testing and pathway scores derived within the same sample. We analysed 1295 participants from three chromate-production plants, measured whole-blood total chromium (WB-Cr), and assessed urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), lymphocyte micronucleus frequency (MNF), and mitochondrial DNA copy number (mtDNA-CN) as complementary response biomarkers. Thirty-four single-nucleotide polymorphisms (SNPs) in 16 genes across six DNA-repair pathways were evaluated using single-variant models, interactions with ln(WB-Cr), pathway-specific genetic risk scores (GRSs), exploratory mediation, functional annotation, and Bayesian kernel machine regression. Primary additive analyses were separated from secondary models and evaluated using prespecified false-discovery-rate (FDR) families, repeated cross-fitting, missing-data analyses, and multi-chain diagnostics. WB-Cr was positively associated with all three biomarkers. Four additive homologous recombination repair (HRR) interactions with ln(WB-Cr) for mtDNA-CN met outcome-specific 34-test FDR control: NBN rs2735383, rs13312840, and rs13312986, and XRCC2 rs3218385. Only XRCC2 rs3218385 remained significant after correction across both the 102-test additive family (q = 0.005) and all 306 model-specific tests (q = 0.007). Cross-fitting did not reproduce the direction of the internally aligned HRR score estimate and did not meet pathway-level FDR control. Exploratory mediation identified an indirect association of WB-Cr with mtDNA-CN through 8-OHdG. These analyses prioritise HRR-related variants for independent replication while distinguishing measured total chromium from the occupational Cr(VI)-exposure context. Synopsis: Within an occupational Cr(VI)-exposure setting, measured whole-blood total chromium was associated with complementary response biomarkers, and multiplicity-controlled analyses identified HRR-related interaction signals for independent replication.