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Dong X.S.,Peoples Hospital of Beijing University | Ma S.F.,CAS Beijing Institute of Genomics | Cao C.W.,CAS Beijing Institute of Genomics | Li J.,Peoples Hospital of Beijing University | And 10 more authors.
Sleep Medicine | Year: 2013

Background: To test if the hypocretin (orexin) neuropeptide precursor (HCRT) gene, HCRT, mutations are implicated in the development of narcolepsy with cataplexy deficiency in young children. Methods: The entire HCRT gene and ∼2000 bp promoter region was first sequenced in 181 patients and 153 controls, and rare polymorphisms including three nonsynonymous amino acid changes were identified. Next the 557 bp region of exon 2 harboring the three nonsynonymous changes was sequenced in an additional 298 early-onset subjects and in 148 control samples. Results: A previously known common polymorphism (rs760282) and nine rare novel polymorphisms were identified in subjects and controls without significant differences. Two nonsynonymous exon 2 substitutions (+977 H54A, +979 G55R) were detected in two subjects with early onset at 7 and 6 years, respectively, but were not found in any controls. These substitutions are not likely to vastly change peptide binding to hypocretin receptors. One additional exon 2 substitution (+1019, K68R) was found in two patients and one control. Additional sequencing that focused on exon 2 showed additional subjects and controls with the +1019 K68R polymorphism and without significant differences between the subjects and the control. Segregation of two of these three nonsynonymous single nucleotide polymorphisms (SNPs) were observed from unaffected parents to offspring. Conclusions: Sequencing of a large number of early-onset narcolepsy subjects revealed three novel nonsynonymous substitutions within the preprohypocretin protein, two of which were only found in patients with early-onset narcolepsy but are not likely to be functionally significant, especially in heterozygote subjects. © 2013 Elsevier B.V. Source


Manber R.,Psychiatry and Behavioral science | Trockel M.,Psychiatry and Behavioral science | Batdorf W.,Health-U | Siebern A.T.,Stanford Center for Sleep science and Medicine | And 4 more authors.
Sleep Medicine Clinics | Year: 2013

Cognitive behavioral therapy for insomnia (CBT-I) is a highly effective and well-established treatment, but patient access is limited because few clinicians are trained to deliver the therapy. The Veterans Health Administration (VHA) is nationally disseminating CBT-I as part of its efforts to make evidence-based psychotherapies widely available to Veterans. As part of this dissemination effort, the VHA has implemented a national, competency-based CBT-I training program. This article describes the training methods and the impact of training on therapists' use of CBT-I and on their self-efficacy to deliver and attitudes toward CBT-I. © 2013 Elsevier Inc. Source


Han F.,Peoples Hospital of Beijing University | Lin L.,Stanford Center for Sleep science and Medicine | Li J.,Peoples Hospital of Beijing University | Dong S.X.,Peoples Hospital of Beijing University | And 11 more authors.
Tissue Antigens | Year: 2012

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility. © 2012 John Wiley & Sons A/S. Source


Faraco J.,Stanford Center for Sleep science and Medicine | Mignot E.,Stanford Center for Sleep science and Medicine
Sleep Medicine Clinics | Year: 2011

Narcolepsy is characterized by excessive daytime sleepiness, symptoms of dissociated REM sleep (sleep paralysis, hypnagogic hallucinations), disrupted nocturnal sleep, and cataplexy (brief episodes of muscle weakness triggered by emotions). Onset of narcolepsy is most often in childhood, peaking between 10 and 25 years of age, and once established the disease is life-long. Significant strides have recently been made in understanding narcolepsy, which can now formally be considered an autoimmune disease based the identification of strong predisposing genetic variants within the HLA and T-cell receptor loci, as well as the identification of increased levels of specific autoantibodies near disease onset. © 2011 Elsevier Inc. All rights reserved. Source


Li J.,Childrens Hospital of Philadelphia | Jorgensen S.F.,University of Oslo | Maggadottir S.M.,Childrens Hospital of Philadelphia | Bakay M.,Childrens Hospital of Philadelphia | And 41 more authors.
Nature Communications | Year: 2015

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10-9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10-16). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition. © 2015 Macmillan Publishers Limited. All rights reserved. Source

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