PMID- 37380713
OWN - NLM
STAT- MEDLINE
DCOM- 20230630
LR  - 20230702
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Jun 28
TI  - Narcolepsy type I-associated DNA methylation and gene expression changes in the 
      human leukocyte antigen region.
PG  - 10464
LID - 10.1038/s41598-023-37511-4 [doi]
LID - 10464
AB  - Narcolepsy type 1 (NT1) is caused by a loss of hypothalamic orexin-producing 
      cells, and autoreactive CD4(+) and CD8(+) T cells have been suggested to play a 
      role in the autoimmune mechanism. Although NT1 showed a strong association with 
      human leukocyte antigen (HLA)-DQB1*06:02, the responsible antigens remain 
      unidentified. We analyzed array-based DNA methylation and gene expression data 
      for the HLA region in CD4(+) and CD8(+) T cells that were separated from the 
      peripheral blood mononuclear cells of Japanese subjects (NT1, N = 42; control, 
      N = 42). As the large number of SNPs in the HLA region might interfere with the 
      affinity of the array probes, we conducted a comprehensive assessment of the 
      reliability of each probe. The criteria were based on a previous study reporting 
      that the presence of frequent SNPs, especially on the 3' side of the probe, makes 
      the probe unreliable. We confirmed that 90.3% of the probes after general 
      filtering in the HLA region do not include frequent SNPs, and are thus suitable 
      for analysis, particularly in Japanese subjects. We then performed an association 
      analysis, and found that several CpG sites in the HLA class II region of the 
      patients were significantly hypomethylated in CD4(+) and CD8(+) T cells. This 
      association was not detected when the effect of HLA-DQB1*06:02 was considered, 
      suggesting that the hypomethylation was possibly derived from HLA-DQB1*06:02. 
      Further RNA sequencing revealed reduced expression levels of HLA-DQB1 alleles 
      other than HLA-DQB1*06:02 in the patients with NT1. Our results suggest the 
      involvement of epigenetic and expressional changes in HLA-DQB1 in the 
      pathogenesis of NT1.
CI  - (c) 2023. The Author(s).
FAU - Yoshida-Tanaka, Kugui
AU  - Yoshida-Tanaka K
AD  - Department of Human Genetics, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan.
FAU - Shimada, Mihoko
AU  - Shimada M
AD  - Genome Medical Science Project (Toyama), National Center for Global Health and 
      Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. 
      mihshimada@ri.ncgm.go.jp.
FAU - Honda, Yoshiko
AU  - Honda Y
AD  - Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo 
      Metropolitan Institute of Medical Science, Tokyo, Japan.
FAU - Fujimoto, Akihiro
AU  - Fujimoto A
AD  - Department of Human Genetics, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan.
FAU - Tokunaga, Katsushi
AU  - Tokunaga K
AD  - Genome Medical Science Project (Toyama), National Center for Global Health and 
      Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
FAU - Honda, Makoto
AU  - Honda M
AD  - Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo 
      Metropolitan Institute of Medical Science, Tokyo, Japan.
AD  - Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, Japan.
FAU - Miyagawa, Taku
AU  - Miyagawa T
AD  - Department of Human Genetics, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan.
AD  - Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo 
      Metropolitan Institute of Medical Science, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230628
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Histocompatibility Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Humans
MH  - *CD8-Positive T-Lymphocytes
MH  - DNA Methylation
MH  - Leukocytes, Mononuclear
MH  - Reproducibility of Results
MH  - Histocompatibility Antigens
MH  - Histocompatibility Antigens Class II
MH  - *Narcolepsy/genetics
MH  - Gene Expression
PMC - PMC10307834
COIS- Dr. Honda has received consultant fees from Takeda Pharmaceutical Company, 
      Alfresa Pharma Corporation, Aculys Pharma Inc., and Ono Pharmaceutical Company 
      for work completely unrelated to this research. None of the other authors have 
      any financial conflicts of interest to disclose.
EDAT- 2023/06/29 01:08
MHDA- 2023/06/30 06:42
PMCR- 2023/06/28
CRDT- 2023/06/28 23:20
PHST- 2023/03/10 00:00 [received]
PHST- 2023/06/22 00:00 [accepted]
PHST- 2023/06/30 06:42 [medline]
PHST- 2023/06/29 01:08 [pubmed]
PHST- 2023/06/28 23:20 [entrez]
PHST- 2023/06/28 00:00 [pmc-release]
AID - 10.1038/s41598-023-37511-4 [pii]
AID - 37511 [pii]
AID - 10.1038/s41598-023-37511-4 [doi]
PST - epublish
SO  - Sci Rep. 2023 Jun 28;13(1):10464. doi: 10.1038/s41598-023-37511-4.