PCCA variant rs16957301 is a novel AKI risk genotype-specific for patients who receive ICI treatment: Real-world evidence from all of us cohort.
Yanfei Wang, Chenxi Xiong, Weifeng Yu, Minghao Zhou, Tyler Shugg, Fang-Chi Hsu, Michael T Eadon, Jing Su, Qianqian Song
Author Information
Yanfei Wang: Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, FL, USA.
Chenxi Xiong: Department of Biostatistics and Health Data Science, Indiana University School of Medicine, IN, USA; Department of Computer and Information Technology, Purdue University, IN, USA.
Weifeng Yu: Department of Computer Science, University of Virginia, VA, USA.
Minghao Zhou: Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, FL, USA.
Tyler Shugg: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, IN, USA.
Fang-Chi Hsu: Biostatistics and Data Science, Wake Forest School of Medicine, NC, USA.
Michael T Eadon: Department of Medicine, Indiana University School of Medicine, IN, USA.
Jing Su: Department of Biostatistics and Health Data Science, Indiana University School of Medicine, IN, USA. Electronic address: su1@iu.edu.
Qianqian Song: Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, FL, USA. Electronic address: qsong1@ufl.edu.
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.
