{"doi":"10.1016/j.ejca.2024.115114","title":"PCCA variant rs16957301 is a novel AKI risk genotype-specific for patients who receive ICI treatment: Real-world evidence from all of us cohort","abstract":"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.","journal":"European Journal of Cancer","year":2024,"id":450927,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1271911,"name":"Chenxi Xiong","orcid":null,"position":1,"is_corresponding":false},{"id":1271408,"name":"Weifeng Yu","orcid":"0000-0002-6408-2338","position":2,"is_corresponding":false},{"id":1271409,"name":"Minghao Zhou","orcid":"0000-0001-5555-8800","position":3,"is_corresponding":false},{"id":340350,"name":"Tyler Shugg","orcid":"0000-0002-5784-3565","position":4,"is_corresponding":false},{"id":291317,"name":"Fang‐Chi Hsu","orcid":"0000-0002-3310-184X","position":5,"is_corresponding":false},{"id":307583,"name":"Michael T. Eadon","orcid":"0000-0003-3066-2876","position":6,"is_corresponding":false},{"id":1271410,"name":"Su Jing","orcid":"0000-0002-0131-9801","position":7,"is_corresponding":false},{"id":288146,"name":"Qianqian Song","orcid":"0000-0002-4455-5302","position":8,"is_corresponding":false},{"id":1271407,"name":"Yanfei Wang","orcid":"0000-0002-9226-8279","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:02:28.969209Z","pmid":"39536432","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}