PCCA 变异 rs16957301 是一种新型 AKI 风险基因型，特异性针对接受 ICI 治疗的患者：来自 ALL of US 队列的真实世界证据。
PCCA variant rs16957301 is a novel AKI risk genotype-specific for patients who receive ICI treatment: Real-world evidence from all of us cohort.
机构信息
Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, FL, USA.
Department of Biostatistics and Health Data Science, Indiana University School of Medicine, IN, USA; Department of Computer and Information Technology, Purdue University, IN, USA.
出版信息
Eur J Cancer. 2024 Dec;213:115114. doi: 10.1016/j.ejca.2024.115114. Epub 2024 Nov 9.
INTRODUCTION
Immune checkpoint inhibitors (ICIs) enhance the immune system's ability to target and destroy cancer cells, but can also trigger immune-related adverse events (irAEs), such as acute kidney injury (ICI-AKI), complicating patient management. Limited knowledge of genetic predispositions to ICI-AKI highlights the need for genomic studies to improve therapeutic strategies.
OBJECTIVE
To identify genetic predispositions for ICI-AKI using large-scale real-world data.
METHODS
A systematic literature search led to 14 candidate variants related to irAEs. We performed a candidate variant association study with these variants using the All of Us cohort. An ICI-treated cohort and a general cohort were established to evaluate ICI-AKI risk. Logistic regression, adjusted for sex, evaluated the impact of each candidate genotype, separately for self-reported and ancestry-estimated race. Kaplan-Meier survival analysis assessed genetic effects on AKI-free survival.
RESULTS
The ICI cohort (n = 414) showed a one-year AKI incidence rate of 23.2 %, significantly higher than the general cohort (6.5 %, n = 213,282). The rs16957301 variant (chr13:100324308, T > C) in the PCCA gene was a significant risk genotype for ICI-AKI among self-reported White (Beta=0.93, CI: 0.32 - 1.54, ORs= 2.53, Bonferroni-corrected P-value=0.047) and ancestry estimated Europeans (Beta = 0.94, CI: 0.31 - 1.57, ORs= 2.56, Bonferroni-corrected P-value=0.044). Self-reported White with the rs16957301 risk genotypes (TC/CC) developed AKI significantly earlier (3.6 months) compared to the reference genotype (TT, 7.0 months, log-rank P = 0.04). Consistent results were found in ancestry-estimated Europeans. This variant did not present significant AKI risks in the general cohort (Beta: -0.008-0.035, FDR: 0.75-0.99).
CONCLUSION
Our findings suggest that rs16957301 in PCCA may serve as an ICI-AKI risk marker in Caucasians. Further studies are needed to validate this association and explore risks in other populations.
简介
免疫检查点抑制剂（ICIs）增强了免疫系统靶向和破坏癌细胞的能力，但也可能引发免疫相关的不良事件（irAEs），如急性肾损伤（ICI-AKI），从而使患者的管理复杂化。对 ICI-AKI 遗传易感性的了解有限，突出了基因组研究对于改善治疗策略的必要性。
目的
使用大规模真实世界数据确定 ICI-AKI 的遗传易感性。
方法
系统文献检索导致了 14 个与 irAEs 相关的候选变异。我们使用 All of Us 队列对这些变异进行了候选变异关联研究。建立了 ICI 治疗队列和一般队列来评估 ICI-AKI 风险。逻辑回归，调整了性别，分别评估了每个候选基因型对自我报告和祖先估计种族的影响。Kaplan-Meier 生存分析评估了遗传对 AKI 无事件生存的影响。
结果
ICI 队列（n=414）的一年 AKI 发生率为 23.2%，明显高于一般队列（n=213282，6.5%）。PCCA 基因中的 rs16957301 变异（chr13:100324308，T>C）在自我报告的白人（Beta=0.93，CI：0.32-1.54，ORs=2.53，Bonferroni 校正 P 值=0.047）和祖先估计的欧洲人中是 ICI-AKI 的显著风险基因型（Beta=0.94，CI：0.31-1.57，ORs=2.56，Bonferroni 校正 P 值=0.044）。具有 rs16957301 风险基因型（TC/CC）的自我报告的白人发生 AKI 的时间明显早于参考基因型（TT，7.0 个月，对数秩检验 P=0.04）。在祖先估计的欧洲人中也得到了一致的结果。该变体在一般队列中并未表现出显著的 AKI 风险（Beta：-0.008-0.035，FDR：0.75-0.99）。
结论
我们的研究结果表明，PCCA 中的 rs16957301 可能是白种人中的 ICI-AKI 风险标志物。需要进一步的研究来验证这种关联，并探索其他人群的风险。
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