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Genetic evidence for POR-mediated ferroptosis in lung cancer prevention: a causal role of granulocyte modulation
Lujie Qian1,2, Linyu Wu1, Xinjing Lou1
1The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 54 Youdian Road, Hangzhou, 310006, People's Republic of China.
Background:
Cytochrome P450 oxidoreductase (POR) plays a vital role in ferroptosis within lung cancer. A potential link exists between ferroptosis-related genes and immune cell activity. This research aimed to confirm whether POR influences lung cancer by modulating immune cells.
Methods:
Genetic variants of the POR gene were identified from lung tissue expression quantitative trait loci (eQTL) data using single nucleotide polymorphisms (SNPs). A genome-wide study of 40,187 Europeans found variants linked to lung cancer. Mediation analysis on 731 immunophenotypes was done to assess their mediating effect on the POR gene-lung cancer relationship.
Results:
This study identified four SNPs for further investigation. Mediation analysis suggested that three immune cell traits might mediate the effect of POR on lung cancer, with CD11c on granulocyte showing a clear mediation effect (β12 = - 0.01, mediation proportion = 8.18%). There was a negative correlation between CD11c on granulocyte and the POR gene (β1 = - 0.23), as well as a positive correlation between CD11c on granulocyte and lung cancer risk (β2 = 0.05).
Conclusions:
Our analysis revealed that increased expression in the POR gene was linked to a lower genetically predicted risk of lung cancer, with a significant mediation effect by the CD11c on granulocyte.
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