Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, The Second Affiliated Chengdu Hospital of Chongqing Medical University, Chengdu 610000, China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113269. doi: 10.1016/j.intimp.2024.113269. Epub 2024 Oct 1.
Programmed death protein 1 (PD-1) inhibitors have potent anti-tumor activities. However, they often result in immune-related adverse events (irAEs) of varying severity. Therefore, the factors affecting the incidence of irAEs warrant urgent investigation. This study aimed to identify specific and sensitive predictors of irAEs in a Chinese population. We conducted a genome-wide association study (GWAS) comprising 80 patients with malignant tumors to evaluate single-nucleotide polymorphism (SNP) loci associated with the incidence of irAEs. The SNP rs2157775 on the LOC339166 gene had the lowest P value but did not reach the significance threshold after Bonferroni correction. Therefore, potentially associated SNPs were further investigated through the mechanism-related PD-1 pathway using the ImmPort and PathCards Human Gene Databases. A binary logistic regression model revealed that CD3E (rs3782040) A/A was associated with a lower incidence of irAEs in patients with malignant tumors who received PD-1 inhibitors. In contrast, PTPN11 (rs143894582) C/CA was associated with a higher incidence of irAEs. These findings provide a basis for the verification and identification of new loci to provide insight into the etiology of irAEs.
程序性死亡蛋白 1（PD-1）抑制剂具有很强的抗肿瘤活性。然而，它们经常导致不同严重程度的免疫相关不良反应（irAEs）。因此，影响 irAEs 发生率的因素值得紧急研究。本研究旨在确定中国人群中 irAEs 的特定和敏感预测因子。我们进行了一项包含 80 名恶性肿瘤患者的全基因组关联研究（GWAS），以评估与 irAEs 发生率相关的单核苷酸多态性（SNP）位点。LOC339166 基因上的 SNP rs2157775 具有最低的 P 值，但在经过 Bonferroni 校正后未达到显著阈值。因此，通过使用 ImmPort 和 PathCards 人类基因数据库对与 PD-1 通路相关的机制，进一步研究了潜在相关的 SNP。二元逻辑回归模型显示，接受 PD-1 抑制剂治疗的恶性肿瘤患者中，CD3E（rs3782040）A/A 与 irAEs 发生率较低相关。相比之下，PTPN11（rs143894582）C/CA 与 irAEs 发生率较高相关。这些发现为验证和识别新的位点提供了依据，为 irAEs 的病因学提供了新的认识。
