Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region
Abstract 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...
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Nature Portfolio
2023-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-37511-4 |
| _version_ | 1827910892328583168 |
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| author | Kugui Yoshida-Tanaka Mihoko Shimada Yoshiko Honda Akihiro Fujimoto Katsushi Tokunaga Makoto Honda Taku Miyagawa |
| author_facet | Kugui Yoshida-Tanaka Mihoko Shimada Yoshiko Honda Akihiro Fujimoto Katsushi Tokunaga Makoto Honda Taku Miyagawa |
| author_sort | Kugui Yoshida-Tanaka |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T01:56:55Z |
| format | Article |
| id | doaj.art-f19c9790267044e7a445e0b068fb32ca |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T01:56:55Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f19c9790267044e7a445e0b068fb32ca2023-07-02T11:13:05ZengNature PortfolioScientific Reports2045-23222023-06-0113111210.1038/s41598-023-37511-4Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen regionKugui Yoshida-Tanaka0Mihoko Shimada1Yoshiko Honda2Akihiro Fujimoto3Katsushi Tokunaga4Makoto Honda5Taku Miyagawa6Department of Human Genetics, Graduate School of Medicine, The University of TokyoGenome Medical Science Project (Toyama), National Center for Global Health and MedicineSleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical ScienceDepartment of Human Genetics, Graduate School of Medicine, The University of TokyoGenome Medical Science Project (Toyama), National Center for Global Health and MedicineSleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical ScienceDepartment of Human Genetics, Graduate School of Medicine, The University of TokyoAbstract 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.https://doi.org/10.1038/s41598-023-37511-4 |
| spellingShingle | Kugui Yoshida-Tanaka Mihoko Shimada Yoshiko Honda Akihiro Fujimoto Katsushi Tokunaga Makoto Honda Taku Miyagawa Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region Scientific Reports |
| title | Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region |
| title_full | Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region |
| title_fullStr | Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region |
| title_full_unstemmed | Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region |
| title_short | Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region |
| title_sort | narcolepsy type i associated dna methylation and gene expression changes in the human leukocyte antigen region |
| url | https://doi.org/10.1038/s41598-023-37511-4 |
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