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A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients received PD-1/PD-L1 inhibitors

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Pubmed体系：
作者：
Lei She[1,2,3] * ; Juan Chen[1,2,4] * ; Jun-Yan Liu[5] * ; Jia-Si Liu[6] ; Xiao-Ping Tang[7] ; Zhan Wang[8] ; Qian Liu[9] ; Lin Su[3] ; Chen-Wei Liao[10] ; Ting Zou[11] ; Zhao Zhang[12] ; Ying Gao[13] ; Yang Gao[14] ; Xiang-Ping Li[1,4] ; Shi-Long Jiang[1,4] ; Wei Zhang[1,2,15] ; Wen-Hui Liu[16] ; Yan Huang[17] ; Nong Yang[18] ; Hong-Hao Zhou[1,2,15] ; Jian-Ting Zhang[19] ; Howard L. McLeod[20] ; Heng Xu[21] ; Fan Yang[22] ; Bai-Mei He[13,*4] ; Pin-Hua Pan[7,*3] ; Ji-Ye Yin[1,2,15,*2] ; Zhao-Qian Liu[1,2,10,15,23,*1] ;
机构： [1]Departments of Clinical Pharmacology and Pharmacy, Xiangya Hospital, Central South University, Changsha 410078, P. R. China [2]Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [3]Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [4]The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha 410008, P. R. China [5]Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [6]Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China [7]Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [8]Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410031, P. R. China [9]Big Data Institute, Central South University, Changsha 410008, P. R. China [10]Xiangya School of Pharmaceutical Science, Central South University, Changsha 410013 P.R. China [11]National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [12]Xiangya Medical School, Central South University, Changsha, Hunan 410013, P. R. China [13]Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [14]Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [15]Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410008, P. R. China [16]Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410008, P. R. China [17]Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [18]Department of Oncology, The Second People's Hospital of Hunan, Changsha 410007, P. R. China [19]Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA [20]Center for Precision Medicine and Functional Genomics, Utah Tech University, St. George, UT 84770, USA [21]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610000,P. R. China [22]Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250011， P. R. China [23]Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P. R. China.
出处：
DOI： 10.1016/j.canlet.2025.218168
ISSN：

关键词： irAEs GWAS pharmacogenomics PD-1/PD-L1 inhibitors lung cancer pneumonitis anemia thrombocytopenia

摘要：
Use of immune checkpoint inhibitors (ICIs) has significantly improved patients' survival with especially lung cancer. However, immunotherapy-related adverse events (irAEs) frequently occur and negatively impact patients' quality of life. While investigations into genetic predictors of irAEs remain ongoing, no robust genetic loci predictive of these toxicities have been definitively established to date. To investigate the pharmacogenomic markers related to irAEs of PD-1/PD-L1 inhibitors in lung cancer patients, we collected blood specimens from 1,467 patients. After rigorous screening and quality control procedures, 785 of these patients were enrolled in a two-stage genome-wide association study (GWAS). The study comprised an initial discovery phase, in which 455 patients underwent microarray-based analysis, and a subsequent validation phase with an independent cohort of 330 patients. Of 688,783 SNPs genotyped using whole genome-wide microarray screening, 52 SNPs were validated using MassARRAY system. The potential impact of significant variants investigated by eQTL analysis. We identified three novel SNPs that are significantly associated with irAEs of PD-1/PD-L1 inhibitor treatments in these lung cancer patients in both discovery and validation cohorts, rs192921786 (discovery: P = 4.09 × 10-7, OR = 9.57; validation: P = 0.043, OR = 4.42) for pneumonitis, rs2498632 (discovery: P = 1.85 × 10-6, OR = 0.50; validation: P = 0.021, OR = 0.65) for anemia and rs17080141 (discovery: P = 9.11 × 10-7, OR = 3.16; validation: P = 0.027, OR = 1.86) for thrombocytopenia. Lung cancer patients with rs192921786 T allele, rs2498632 C allele, and rs17080141 A allele were more likely to suffer immunotherapy related pneumonitis, anemia and thrombocytopenia, respectively. In conclusion, rs192921786, rs2498632 and rs17080141 are novel candidate risk loci for pneumonitis, anemia, and thrombocytopenia in lung cancer patients receiving immunotherapy. These findings warrant further investigation and validation to assess their potential as predictive biomarkers.Copyright © 2025. Published by Elsevier B.V.

基金：
This work was supported by the National Science and Technology Major Project of China(2023ZD0506900), National Natural Science Foundation of China (82173901), Major Project ofNatural Science Foundation ofHunan Province (Open competition, 2021JC0002), Hunan Provincekey research and development plan of China (2023SK2007), Hunan Provincial Natural ScienceFoundation ofChina (2024118180), China Postdoctoral Science Foundation (2023M733973), andChangsha Municipal Natural Science Foundation (kq2014208, kq2208408)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
最新[2025]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
第一作者：
第一作者机构： [1]Departments of Clinical Pharmacology and Pharmacy, Xiangya Hospital, Central South University, Changsha 410078, P. R. China [2]Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [3]Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
共同第一作者：
通讯作者：
通讯机构： [1]Departments of Clinical Pharmacology and Pharmacy, Xiangya Hospital, Central South University, Changsha 410078, P. R. China [2]Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [7]Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [10]Xiangya School of Pharmaceutical Science, Central South University, Changsha 410013 P.R. China [13]Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [15]Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410008, P. R. China [23]Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P. R. China. [*1]Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, P. R. China [*2]Department of Clinical Pharmacology, Central South University, Changsha 410008,P. R. China [*3]Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, P. R. China [*4]Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
推荐引用方式(GB/T 7714)：
Lei She,Juan Chen,Jun-Yan Liu,et al.A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients received PD-1/PD-L1 inhibitors[J].Cancer Letters.2025,218168.doi:10.1016/j.canlet.2025.218168.
APA：
Lei She,Juan Chen,Jun-Yan Liu,Jia-Si Liu,Xiao-Ping Tang...&Zhao-Qian Liu.(2025).A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients received PD-1/PD-L1 inhibitors.Cancer Letters,,
MLA：
Lei She,et al."A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients received PD-1/PD-L1 inhibitors".Cancer Letters .(2025):218168

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