PCCA Variant Rs16957301 is a Novel AKI Risk Genotype-specific for Patients Who Receive ICI Treatment: Real-world Evidence from All of Us Cohort
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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.
Li S, Liu K, Rong C, Zheng X, Cao B, Guo W J Hepatocell Carcinoma. 2024; 11:2471-2480.
PMID: 39712947 PMC: 11663388. DOI: 10.2147/JHC.S499436.