DQB1*0301 and DQB1*0601 Modulate Narcolepsy Susceptibility in Koreans

Hong, Seung Chul; Lin, Ling; Lo, Betty; Jeong, Jong-Hyun; Shin, Yoon Kyung; Kim, Su Yeon; Kweon, Yong‐Sil; Zhang, Jing; Einen, Mali; Smith, Anajane G.; Hansen, John A.; Grumet, F. Carl; Mignot, Emmanuel

doi:10.1016/j.humimm.2006.10.006

Cited by 67 publications

(66 citation statements)

References 30 publications

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“…Most notably, HLA-DQA1*01:01~DQB1*05:01, HLA-DQA1*01:03~DQB1*06:03, and HLA-DQA1*01:03~DQB1* 06:01 are protective against narcolepsy, whereas DQ0602 homozygosity increases risk in all ethnic groups. 2,3,22,[26][27][28][29] We postulate that this is due to allele competition, a model where risk is proportional to the amount of DQ0602 available and its unique ability to present a putative autoantigen. 3,26 The model also predicts that any minor change in the DQ0602 antigen binding groove abolishes predisposition.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to affecting allele competition, HLA-DQB1* 03:01 increases narcolepsy susceptibility when present in trans of DQ0602, 3,22,26,27,29 an effect unlikely to be explained by allele competition given that HLA-DQB1* 03:01 does not heterodimerize with HLA-DQA1*01:02 and thus should not affect DQ0602 dosage. 30 Unlike DQ0602 dosage, HLA-DQB1*03:01 also strongly reduces age of onset, 2,5 suggesting that it acts through a different mechanism, for example, development of the TCR repertoire.…”

Section: Introductionmentioning

confidence: 99%

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HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

Ollila

Ravel

Han

et al. 2015

The American Journal of Human Genetics

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122

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Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

Ollila

Ravel

Han

et al. 2015

The American Journal of Human Genetics

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122

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“…In China, there is a population prevalence of 0.034% in patients in South China presenting to sleep centers in Hong Kong 1,2 and a prevalence of 0.014% in Korean adolescents with similar clinical and biological presentations. [3][4][5] Studies in North America and Europe estimates are similar. As the origin and mechanisms that produce narcolepsy are not well understood, comparisons of clinical presentations in collections of several characterized patient groups can inform future studies of clinical and genetic epidemiology.…”

Section: Introductionmentioning

confidence: 75%

Presentations of Primary Hypersomnia in Chinese Children

Han

et al. 2011

Sleep

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627Childhood Narcolepsy/Hypersomnia-Han et al on the pediatric population could help address issues related to puberty, genetic predisposition, and environmental triggers, and possibly shed light on factors that might delay diagnosis. We report on findings from a pediatric cohort of patients who presented with primary hypersomnia to a sleep clinic in Beijing, China over a period of ~10 years. All were evaluated in a standard fashion and classified as narcolepsy with or without cataplexy or idiopathic hypersomnia. Our purpose was to describe age of onset and clinical features of primary hypersomnia among a mainland Chinese cohort of children, and to compare the findings to the literature. METHODS PatientsPatients were children, defined as < 18 years of age, successively presenting with hypersomnia seen over a period of ~10 years (September, 1998 to May, 2009) at People's Hospital, Beijing University, Beijing. A total of 417 children (63%) were drawn from a population of 671 adults and children with hypersomnia. The hospital has a pulmonary medicine departmentbased sleep center, which sees both children and adults, and receives referrals from all of mainland China. It is estimated that 70% of the diagnosed narcolepsy patients in mainland China are seen at this center at People's Hospitals.12 A prior report focused on the impact of a narcolepsy recognition strategy in a pediatric neurology clinic, 13 whereas this report retrospectively describes a cohort with a broader symptom profile, evaluated using a stan- INTRODUCTIONNarcolepsy-cataplexy (NC) occurs worldwide. In China, there is a population prevalence of 0.034% in patients in South China presenting to sleep centers in Hong Kong 1,2 and a prevalence of 0.014% in Korean adolescents with similar clinical and biological presentations.3-5 Studies in North America and Europe estimates are similar. As the origin and mechanisms that produce narcolepsy are not well understood, comparisons of clinical presentations in collections of several characterized patient groups can inform future studies of clinical and genetic epidemiology.Narcolepsy-cataplexy is said to present in the second to third decade of life, with 70% to 80% of patients reporting onset between 10-20 years of age. Large sample size observations from the United States, Canada, Europe, and Japan report that half of adult patients with narcolepsy report narcolepsy onset prior to 15 years old, and only exceptionally at 5 or younger.6-9 Studies in the 1980s-1990s reported a median delay > 10 years between onset and diagnosis, 10 whereas a more recent report suggests the delay can be only a few years, particularly in children.11 A focus Objective: To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population. Methods: A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) ...

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“…All patients completed a validated questionnaire predictive of cataplexy, the Center for Narcolepsy Sleep Inventory (SSI), a validated questionnaire predictive of cataplexy [15]. Hypocretin deficiency was documented in 37 patients (all DQB1*0602 positive) through cerebrospinal fluid (CSF) hypocretin-1 evaluation, while the other 93 patients were selected based on DQB1*0602 positivity and the presence of cataplexy, as described in HONG et al [16]. .95% of DQB1*0602-positive narcolepsy-cataplexy patients have hypocretin deficiency [17].…”

Section: Methodsmentioning

confidence: 99%

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status

Han¹,

Mignot²,

Wei³

et al. 2010

European Respiratory Journal

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We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean¡SD age 20¡10 yrs, 69% male) and 117 controls (22¡6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (DV9E)/carbon dioxide tension (DPCO 2 ) L?min KEYWORDS: Chemoresponsiveness, human leukocyte antigen DQB1, hypercapnia, hypoxia, narcolepsy H ypoxic and hypercapnic sensing are processed through neuromuscular circuits resulting in an increase or decrease of tidal volume, respiratory frequency and minute ventilation (V9E). Such chemosensory reflexes operate to influence sleep apnoea, chronic obstructive pulmonary disease (COPD), heart failure, and acute adaptation to high altitude [1]. A variation in chemosensitivity across various inbred rodent strains and familial clustering of ventilatory traits in humans provides a strong rationale for gene and protein isolation efforts to unravel molecular mechanisms for these traits operating in health and disease [2].Hypocretin (orexin) is a hypothalamic neurotransmitter, which, when given intracerebroventricularly in mice, promotes both wakefulness and ventilation [3,4]. Both hypocretin knockout and hypocretin neuron-ablated mice show attenuation of respiratory excitation during fightor-flight responses [5]. Particular to chemoresponsiveness, hypocretin/orexin knockout mice have attenuated hypercapnic ventilatory responses [6]; supplementation of hypocretin-1 or -2 partially restores an attenuated response to hypercapnia, while administration of hypocretin receptor-1 antagonist will reduce hypercapnic responsiveness in wild type mice [7]. Post-hypoxic long-term facilitation, a physiological feature that is presumed to reduce sleep apnoea, is absent in hypocretin/orexin knockout mice [8].The human model of hypocretin deficiency is narcolepsy with cataplexy [9,10]. This disorder is also associated with the gene marker, human leukocyte antigen (HLA)-DQB1*0602 [11]. This disease is also considered to be associated with a higher expression of sleep-disordered breathing [12,13]. Our primary hypothesis was that an impaired chemoresponsiveness would be present

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DQB10301 and DQB10601 Modulate Narcolepsy Susceptibility in Koreans

Cited by 67 publications

References 30 publications

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

Presentations of Primary Hypersomnia in Chinese Children

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status

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