An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population

Miyagawa, Taku; Toyoda, Hiromi; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Ikegami, Azusa; Wada, Yamato; Takami, Masanori; Fujimura, Yota; Tamura, Yoshiyuki; Omata, Naoto; Masuya, Yasuhiro; Kondo, Hideaki; Moriya, Shunpei; Furuya, Hirokazu; Kato, Mitsuhiro; Kojima, Hiroto; Kashiwase, Koichi; Saji, Hiroh; Khor, Seik‐Soon; Yamasaki, Makari; Ishigooka, Jun; Wada, Yuji; Yamada, Naoto; Okawa, Masako; Kuroda, Kenji; Kume, Kazuhiko; Hirata, Koichi; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yoshiyuki; Mishima, Kazuo; Honda, Masashi; Tokunaga, Katsushi

doi:10.1038/hgv.2015.31

Cited by 20 publications

(7 citation statements)

References 23 publications

(33 reference statements)

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“…Taken together, these reports suggest a genetic contribution to IH. However, the strong association between narcolepsy type 1 and HLA DQB1*0602 is not observed in patients with IH, in whom the rate of positivity for this allele ranges from 8–27%, depending on the population, and approximates the rate in controls (4, 18–20). An immune system dysregulation, unique from that implicated in narcolepsy type 1, might be present in patients with IH, as suggested by their significantly increased rates of comorbid inflammatory or allergic disorders (17, 21) and altered IgG profile compared to controls (22).…”

Section: Introductionmentioning

confidence: 94%

Idiopathic Hypersomnia

Trotti

2017

Sleep Medicine Clinics

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Idiopathic hypersomnia (IH) is a chronic neurological disorder that results in daytime sleepiness, frequently accompanied by long nocturnal or daytime sleep, unrefreshing sleep, difficulty in awakening, cognitive dysfunction, and autonomic symptoms. The cause of idiopathic hypersomnia is presently unknown, although a genetic predisposition is suggested by the strong family history of similar symptoms. Dysfunction of autonomic, inflammatory, or immune systems has been proposed, and patients with IH have been found to have an endogenous modulator of GABA-A receptors within their cerebrospinal fluid. Diagnosis of IH involves a careful clinical history, with particular attention to the possibility of other disorders with similar symptomatology, and objective testing with actigraphy, polysomnography, and multiple sleep latency testing. There are no FDA-approved treatments for IH symptoms, which are typically treated with off-label use of medications approved for narcolepsy. Modafinil is first line and supported by two randomized, controlled trials in IH patients. A substantial fraction of IH patients are refractory or intolerant to standard treatments, and different treatment strategies, employing novel therapeutics, are necessary in these cases. Even with current treatment options, quality of life and safety may remain impaired in patients with this challenging chronic disease.

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Section: Introductionmentioning

confidence: 94%

Idiopathic Hypersomnia

Trotti

2017

Sleep Medicine Clinics

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“…NT2 is also associated with DQB1 * 06:02 . Thirty to 50% of patients with NT2 are DQB1 * 06:02- positive, and the frequency is significantly higher than that in the general population but is lower than that in NT1 (Table 1) 20,22–24 .…”

Section: Strong Association Between Nt1 and Human Leukocyte Antigen (mentioning

confidence: 90%

Genetics of narcolepsy

Miyagawa

Tokunaga

2019

Hum Genome Var

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Narcolepsy is a term that was initially coined by Gélineáu in 1880 and is a chronic neurological sleep disorder that manifests as a difficulty in maintaining wakefulness and sleep for long periods. Currently, narcolepsy is subdivided into two types according to the International Classification of Sleep Disorders, 3rd edition: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). NT1 is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis and is caused by a marked reduction in neurons in the hypothalamus that produce orexin (hypocretin), which is a wakefulness-associated neuropeptide. Except for cataplexy, NT2 exhibits most of the same symptoms as NT1. NT1 is a multifactorial disease, and genetic variations at multiple loci are associated with NT1. Almost all patients with NT1 carry the specific human leukocyte antigen (HLA) allele HLA-DQB1*06:02. Genome-wide association studies have uncovered >10 genomic variations associated with NT1. Rare variants associated with NT1 have also been identified by DNA genome sequencing. NT2 is also a complex disorder, but its underlying genetic architecture is poorly understood. However, several studies have revealed loci that increase susceptibility to NT2. The currently identified loci cannot explain the heritability of narcolepsy (NT1 and NT2). We expect that future genomic research will provide important contributions to our understanding of the genetic basis and pathogenesis of narcolepsy.

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“…The HLA-DQB1 gene is responsible for exogenous peptide presentation and encodes one of the two components of the HLA-DQ molecule, which regulates T cell response to islet cell autoantigens [23,24]. In fact, HLA-DQB1 alleles have been identified as susceptibility loci for type I diabetes, celiac disease, multiple sclerosis, and narcolepsy [22,[25][26][27][28]. With regard to AS, HLA-DQB1 was previously associated with the age of onset and severity of AS in a Han Chinese population [29].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression analysis of ankylosing spondylitis shows deregulation of the HLA-DRB, HLA-DQB, ITM2A, and CTLA4 genes

AlEjielat

Khaleel

Tarkhan³

2021

Egypt J Med Hum Genet

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Background Ankylosing spondylitis (AS) is a rare inflammatory disorder affecting the spinal joints. Although we know some of the genetic factors that are associated with the disease, the molecular basis of this illness has not yet been fully elucidated, and the genes involved in AS pathogenesis have not been entirely identified. The current study aimed at constructing a gene network that may serve as an AS gene signature and biomarker, both of which will help in disease diagnosis and the identification of therapeutic targets. Previously published gene expression profiles of 16 AS patients and 16 gender- and age-matched controls that were profiled on the Illumina HumanHT-12 V3.0 Expression BeadChip platform were mined. Patients were Portuguese, 21 to 64 years old, were diagnosed based on the modified New York criteria, and had Bath Ankylosing Spondylitis Disease Activity Index scores > 4 and Bath Ankylosing Spondylitis Functional Index scores > 4. All patients were receiving only NSAIDs and/or sulphasalazine. Functional enrichment and pathway analysis were performed to create an interaction network of differentially expressed genes. Results ITM2A, ICOS, VSIG10L, CD59, TRAC, and CTLA-4 were among the significantly differentially expressed genes in AS, but the most significantly downregulated genes were the HLA-DRB6, HLA-DRB5, HLA-DRB4, HLA-DRB3, HLA-DRB1, HLA-DQB1, ITM2A, and CTLA-4 genes. The genes in this study were mostly associated with the regulation of the immune system processes, parts of cell membrane, and signaling related to T cell receptor and antigen receptor, in addition to some overlaps related to the IL2 STAT signaling, as well as the androgen response. The most significantly over-represented pathways in the data set were associated with the “RUNX1 and FOXP3 which control the development of regulatory T lymphocytes (Tregs)” and the “GABA receptor activation” pathways. Conclusions Comprehensive gene analysis of differentially expressed genes in AS reveals a significant gene network that is involved in a multitude of important immune and inflammatory pathways. These pathways and networks might serve as biomarkers for AS and can potentially help in diagnosing the disease and identifying future targets for treatment.

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An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population

Cited by 20 publications

References 23 publications

Idiopathic Hypersomnia

Idiopathic Hypersomnia

Genetics of narcolepsy

Differential gene expression analysis of ankylosing spondylitis shows deregulation of the HLA-DRB, HLA-DQB, ITM2A, and CTLA4 genes

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