PMID- 36177028
OWN - NLM
STAT- MEDLINE
DCOM- 20221003
LR  - 20221012
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Association between germ-line HLA and immune-related adverse events.
PG  - 952099
LID - 10.3389/fimmu.2022.952099 [doi]
LID - 952099
AB  - BACKGROUND: In recent years, significant progress has been made in immune 
      checkpoint inhibitors (ICIs). However, accompanied by remarkable efficacy, a 
      growing number of immune-related adverse events (irAEs) also arose. The mechanism 
      of irAEs remains unclear. Previous studies indicated a positive association 
      between specific human leukocyte antigen (HLA) variants and irAEs. Therefore, we 
      planned and initiated a large cohort study aiming to uncover the relationship 
      between irAEs and divergent HLA types. METHODS: We screened all patients who have 
      been treated in the clinical research ward, Cancer Hospital of the Chinese 
      Academy of Medical Sciences. All participants were diagnosed with malignant 
      tumors with complete AE follow-up data in the original electronic medical 
      records. Sequencing libraries were generated using a customized panel, and 
      four-digit formatted HLA alleles were extracted for further analysis. Association 
      analysis was performed between HLA variants and different irAEs. We introduced 
      two external reference groups and a non-irAE control group within the study 
      cohort to control the type I error. We also explored the relationship between the 
      zygosity of HLA genes, the evolutionary divergence of HLA class I genotype (HED), 
      and irAEs. RESULTS: 530 participants received at least two doses of ICIs. The 
      median follow-up time was 10.3 months. 97% of patients received anti-PD-1/PD-L1 
      treatment. The occurrence of overall irAEs showed no significant difference 
      between the HLA homozygous group and the HLA heterozygous group. We did not find 
      any significant association between irAEs and HED. We found that some HLA types 
      are associated with irAEs of different organs and detected a significant 
      association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 
      0.011), HLA-DPB1*04:02 and hypokalemia/hyponatremia (OR 3.44 (1.24,9.1), p = 
      0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037), anemia (OR 2.33 (1.0,5.41), p 
      = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). 
      CONCLUSIONS: IrAEs in specific organs and tissues may be associated with certain 
      HLA types, while HLA heterogeneity has no significant influence on the happening 
      of irAEs. More research is needed to explore the role of germline genetic changes 
      in the risk assessment of irAEs.
CI  - Copyright (c) 2022 Jiang, Yu, Zhang, Tang, Wu, Wang, Fang, Zhang, Meng, Li, Miao, 
      Ma, Huang and Li.
FAU - Jiang, Ning
AU  - Jiang N
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Yu, Yue
AU  - Yu Y
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Zhang, Min
AU  - Zhang M
AD  - Oncology Bussiness Department, Novogene Co., Ltd, Beijing, China.
FAU - Tang, Yu
AU  - Tang Y
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Wu, Dawei
AU  - Wu D
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Wang, Shuhang
AU  - Wang S
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Fang, Yuan
AU  - Fang Y
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Research and Development Department, Burning Rock Biotech, Guangzhou, China.
FAU - Meng, Lin
AU  - Meng L
AD  - Oncology Bussiness Department, Novogene Co., Ltd, Beijing, China.
FAU - Li, Yingying
AU  - Li Y
AD  - Oncology Bussiness Department, Novogene Co., Ltd, Beijing, China.
FAU - Miao, Huilei
AU  - Miao H
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Ma, Peiwen
AU  - Ma P
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Huang, Huiyao
AU  - Huang H
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Li, Ning
AU  - Li N
AD  - Clinical Cancer Center, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20220913
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-DRB3 Chains)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - RFM9X3LJ49 (Bilirubin)
SB  - IM
MH  - *Antineoplastic Agents, Immunological/adverse effects/therapeutic use
MH  - B7-H1 Antigen
MH  - Bilirubin
MH  - Cohort Studies
MH  - Germ Cells
MH  - *HLA Antigens/genetics
MH  - HLA-DRB3 Chains
MH  - Humans
MH  - *Immune Checkpoint Inhibitors/adverse effects/therapeutic use
MH  - *Immune System Diseases/drug therapy
PMC - PMC9513190
OTO - NOTNLM
OT  - PD-1
OT  - genotype
OT  - human leukocyte antigen
OT  - immune checkpoint inhibitors
OT  - immune-related adverse events
COIS- Authors MZ, ML and YL are employed by Novogene Co., Ltd, Beijing, China. Author 
      YZ is employed by Burning Rock Biotech, Guangzhou, China. The remaining authors 
      declare that the research was conducted in the absence of any commercial or 
      financial relationships that could be construed as a potential conflict of 
      interest.
EDAT- 2022/10/01 06:00
MHDA- 2022/10/04 06:00
PMCR- 2022/01/01
CRDT- 2022/09/30 02:40
PHST- 2022/05/24 00:00 [received]
PHST- 2022/08/23 00:00 [accepted]
PHST- 2022/09/30 02:40 [entrez]
PHST- 2022/10/01 06:00 [pubmed]
PHST- 2022/10/04 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.952099 [doi]
PST - epublish
SO  - Front Immunol. 2022 Sep 13;13:952099. doi: 10.3389/fimmu.2022.952099. eCollection 
      2022.