A Functional Variant rs2122031 in ATG7 Is Associated with the Risk of Radiation Pneumonitis

Radiation pneumonitis (RP) is characterized by inflammation and is associated with autophagy. However, the relationship between functional genetic variants of autophagy-related genes and RP remains unknown. In this study, we aimed to investigate whether genetic variants of genes involved in autophagy are associated with RP. Genotyping was conducted on a total of 301 patients for 13 SNPs of 5 genes in the autophagy pathway using MassArray and Sanger sequencing. Two radiation oncologists independently measured the degree of RP by chest X-ray or computed tomography. The multivariate Cox hazard analysis and multiple testing showed that ATG7:rs2122031 GA/GG significantly decreased the risk of RP grade ⩾3 (hazard ratio, 0.369; 95% confidence interval, 0.189-0.720; P = 0.003, corrected P = 0.039). Furthermore, qRT-PCR and immunohistochemical analysis demonstrated that the ATG7:rs2122031 AA genotypes were related to decreased expression of ATG7 (autophagy-related protein 7). Loss of autophagy by deletion of ATG7 in fibroblasts or conditional ATG7-knockout mice was proven to increase RP. Single-cell RNA sequencing revealed regulation of autophagy-related genes enriched after irradiation stress in conditional ATG7-knockout mice. Our findings indicated that genetic variants of ATG7 were associated with RP and may therefore be used to predict RP before radiation therapy. Loss of ATG7 was also shown to promote RP, which suggested that ATG7 may be an intervention target for RP.