Cross-ancestry meta-analysis identifies a GSTP1 variant in the polycyclic aromatic hydrocarbons metabolism-related pathway contributing to colorectal cancer susceptibility.

Unhealthy diets (e.g., higher red meat consumption) and tobacco exposure are major risk factors for colorectal cancer (CRC), contributing the toxic substances exposure of polycyclic aromatic hydrocarbons (PAHs). However, the genetic regulation of PAHs metabolism-related genes involved in CRC susceptibility remains unexplored. To address this gap, we performed a meta-analysis using cross-ancestry genome-wide data, including East Asian populations (Chinese: N = 1150, N = 1342; Japanese: N = 6692, N = 27,178) and European (N = 78,473, N = 107,143) to evaluate the genetic association of 47 PAHs-metabolism-related genes with CRC risk. Expression patterns were derived from Nanjing ColoRectal Cancer cohort (NJCRC) and public datasets, including a total of 828 bulk RNA-Seq samples, 62 samples for cell-type-specific expression samples, and 50 paired protein validation samples. Finally, we observed that rs7927381 C > T in GSTP1 was associated with reduced CRC risk (odds ratio (OR) = 0.94, 95% confidence interval (CI) = 0.92-0.96, P = 1.90 × 10). Intriguingly, it downregulated the GSTP1 expression specifically in plasmablast cells. This effect may be attributed to its location in the DNA-hypersensitive regulatory region with enhancer and promoter activity, which could alter transcription factor binding. Notably, both GSTP1 mRNA and protein level were upregulated in CRC tissues, suggesting its elevation may influence PAHs metabolism through the oxidative phosphorylation and ribosome biological processes, promoting carcinogenesis. In conclusion, we identified GSTP1 rs7927381 as a cross-ancestry genetic variant affecting CRC risk through influencing PAHs metabolizing, offering new insights into the genetic mechanisms underlying CRC.