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

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Abstract

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10 ⁻⁷, odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10 ⁻⁸, OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA ( P=5.8×10 ⁻⁷). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

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Most cited references 24

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Hypocretin (orexin) deficiency in human narcolepsy.

S Nishino, B Ripley, S. Overeem … (2000)

Alterations in the hypocretin receptor 2 and preprohypocretin genes produce narcolepsy in animal models. Hypocretin was undetectable in seven out of nine people with narcolepsy, indicating abnormal hypocretin transmission.

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The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

Harald Schrader, Emmanuel Mignot, S Nevsimalova … (2002)

Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

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The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study.

Michael Silber, Lois E Krahn, Eric Olson … (2002)

To determine the age- and sex-specific incidence rates and prevalence of narcolepsy in a United States community. The records-linkage system of the Rochester Epidemiology Project was utilized to ascertain all patients with narcolepsy seen in Olmsted County, Minnesota between 1960 and 1989. Age- and sex-specific incidence rates were calculated, using census data. Prevalence of narcolepsy on January 1,1985 was calculated. N/A. Community patients diagnosed with narcolepsy by a validated set of diagnostic criteria. N/A. The incidence rate per 100,000 persons per year was 1.37 (1.72 for men and 1.05 for women). The incidence rate was highest in the 2nd decade, followed in descending order by the 3rd, 4th and 1st decades. The prevalence on January 1, 1985 was 56.3 per 100,000 persons. Approximately 36% of prevalence cases did not have cataplexy. Narcolepsy is not a rare disorder. It appears to be commoner in men. It originates most commonly in the 2nd decade. Narcolepsy without cataplexy is an important subgroup, warranting further study.

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Journal

Journal ID (nlm-ta): Hum Genome Var

Journal ID (iso-abbrev): Hum Genome Var

Title: Human Genome Variation

Publisher: Nature Publishing Group

ISSN (Electronic): 2054-345X

Publication date (Electronic): 17 September 2015

Publication date Collection: 2015

Volume: 2

Page: 15031

Affiliations

[1 ] Department of Human Genetics, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan

[2 ] Department of Neuropsychiatry, Akita University School of Medicine , Akita, Japan

[3 ] International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba , Ibaraki, Japan

[4 ] Department of Neuropsychiatry, Kurume University School of Medicine , Fukuoka, Japan

[5 ] Kotorii Isahaya Hospital , Nagasaki, Japan

[6 ] Sleep Disorder Center, National Center Hospital, National Center of Neurology and Psychiatry , Tokyo, Japan

[7 ] Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry , Tokyo, Japan

[8 ] Department of Neurology, Dokkyo Medical University , Tochigi, Japan

[9 ] Sleep Center, Kuwamizu Hospital , Kumamoto, Japan

[10 ] Department of Psychiatry, Hannan Hospital , Osaka, Japan

[11 ] Department of Psychiatry, Shiga University of Medical Science , Shiga, Japan

[12 ] Department of Psychiatry and Neurology, Asahikawa Medical University , Hokkaido, Japan

[13 ] Department of General Medicine, Faculty of Medicine, Shimane University , Shimane, Japan

[14 ] Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui , Fukui, Japan

[15 ] Center for Sleep Medicine, Saiseikai Nagasaki Hospital , Nagasaki, Japan

[16 ] Department of Psychiatry, Tokyo Women's Medical University School of Medicine , Tokyo, Japan

[17 ] Department of Neurology, Neuro-Muscular Center, National Omuta Hospital , Fukuoka, Japan

[18 ] Department of Neurology, Kochi Medical School, Kochi University , Kochi, Japan

[19 ] Department of Pediatrics, Yamagata University Faculty of Medicine , Yamagata, Japan

[20 ] Department of Pediatrics, Showa University School of Medicine , Tokyo, Japan

[21 ] HLA Foundation Laboratory , Kyoto, Japan

[22 ] Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center , Tokyo, Japan

[23 ] Department of Sleep Medicine, Shiga University of Medical Science , Shiga, Japan

[24 ] Japan Foundation for Neuroscience and Mental Health , Tokyo, Japan

[25 ] Department of Somnology, Tokyo Medical University , Tokyo, Japan

[26 ] Department of Stem Cell Biology, Institute of Molecular Genetics and Embryology, Kumamoto University , Kumamoto, Japan

[27 ] Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University , Aichi, Japan

[28 ] Japan Somnology Center, Neuropsychiatric Research Institute , Tokyo, Japan

[29 ] Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science , Tokyo, Japan

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[* ] ( miyagawa-taku@ 123456umin.ac.jp )

Article

Publisher Item ID: hgv201531

DOI: 10.1038/hgv.2015.31

PMC ID: 4785567

PubMed ID: 27081540

SO-VID: 3beeffec-90ab-4f88-8567-91f211a6d477

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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

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Most cited references 24

Hypocretin (orexin) deficiency in human narcolepsy.

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study.

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