Cuproptosis-Related Gene-SLC31A1, FDX1 and ATP7B-Polymorphisms are Associated with Risk of Lung Cancer

Background: Cuproptosis is a novel copper-dependent cell death, and the copper level was increased in lung cancer patients. However, few studies evaluated the association between single-nucleotide polymorphisms (SNPs) in cuproptosis-related genes and lung cancer risk.Methods: Six SNPs of the SLC31A1, FDX1 and ATP7B genes were genotyped in a case-control cohort including 650 lung cancer cases and 650 controls using the MassARRAY platform.Results: The minor alleles of SLC31A1-rs10981694 and FDX1-rs10488764 were associated with an increased risk of lung cancer (rs10981694: OR=1.455, 95% CI: 1.201-1.763, p<0.001; rs10488764: OR=1.483, 95% CI: 1.244-1.768, p<0.001). In contrast, the minor alleles of rs9535826 and rs9535828 in ATP7B were related to a decreased risk of the disease (rs9535826: OR=0.714, 95% CI: 0.608-0.838 p<0.001; rs9535828: OR=0.679, 95% CI: 0.579-0.796, p<0.001). The frequencies of rs10981694-TG/GG and rs10488764-GA/AA genotypes were significantly higher in lung cancer cases than that in controls, making them risk genotypes for the disease (p < 0.001); while the rs9535826-TG/GG and rs9535828-GA/AA genotypes were protective genotypes and associated with a reduced risk of the disease (p<0.001). Genetic model evaluation revealed that SLC31A1-rs10981694 and FDX1-rs10488764 were associated with a growing risk of lung cancer in dominant, recessive and log-additive models (p<0.001). Moreover, rs9535826 and rs9535828 in ATP7B were related to a declining risk of the disease in three genetic models (p<0.001). In addition, stratification analysis showed that FDX1-rs10488764 was risk variant for lung cancer in both smokers and nonsmokers, and was associated with risk of each pathological type of lung cancer (p<0.008).Conclusion: The results shed new light on the correlation between cuproptosis-related genes and risk of lung cancer.