Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Síndrome de apnea/hipopnea obstructiva ligado al sueño REM: ¿un diagnóstico olvidado? Posible vía de infradiagnóstico del síndrome de apnea/hipopnea obstructiva del sueño / ‘REM-related OSA’: a forgotten diagnostic? Possible path to under-diagnosing sleep apnea

Introducción. Recientemente se han propugnado criterios restrictivos para definir el síndrome de apnea/hipopnea obstructiva ligado al sueño REM y persisten interrogantes sobre su trascendencia nosológica y manejo clínico. Objetivo. Evaluar los criterios definitorios de la apnea del sueño REM, su relación con la comorbilidad cardiometabólica y los aspectos relacionados con su diagnóstico. Pacientes y métodos. Estudio observacional retrospectivo sobre datos clínicos y polisomnográficos de pacientes ambulatorios. Se incluyó a 525 pacientes mayores de 18 años que tenían un índice apnea/hipopnea (IAH) por hora de sueño ≥ 5 (total, o parcial en REM o no REM). Resultados. Se han configurado subgrupos ‘dependientes de la fase’ utilizando un criterio basado en la ‘proporción ≥ 2’ y otro ‘estricto’ basado en uno de los IAH parciales ≥ 5 frente al otro IAH < 5 (en REM o en no REM). En el subgrupo ‘apnea del sueño REM estricto’, la mitad de los pacientes muestra un IAH global < 5 y menos gravedad en los parámetros respiratorios, pero sin menores porcentajes de comorbilidad. Con los criterios diagnósticos actuales quedarían excluidos del diagnóstico de síndrome de apnea/hipopnea obstructiva del sueño (SAHOS). Conclusiones. Aplicar un criterio estricto para detectar apnea del sueño REM permite filtrar formas muy leves de SAHOS asociadas a comorbilidad cardiometabólica en porcentajes no diferentes significativamente de otras formas más graves. Para evitar el infradiagnóstico del SAHOS sería oportuno revisar los criterios diagnósticos actuales y las indicaciones de las técnicas reducidas (AU)

Introduction. Restrictive criteria are proposed to define the disorder ‘REM-related OSA’ disorder, and questions remain about its nosological transcendence and clinical management. Aim. To evaluate the criteria proposed to define ‘REM-related OSA’, its relationship with cardio-metabolic comorbidity, and aspects related to it diagnostic. Patients and methods. Retrospective observational study of clinical and polysomnographic data from outpatients. 525 patients over 18 years old who had an Apnea Hypopnea Index (AHI) ≥ 5 (total, or partial, in REM and/or NREM) were included. Results. ‘Phase-dependent’ subgroups were formed using a criterion based on the ‘ratio ≥ 2’ and another ‘strict’ criterion based on a partial AHI ≥ 5 compared to another partial AHI <5 (in REM or in NREM). In the ‘strict REM-related OSA’ subgroup, half of the patients showed an overall AHI < 5, with less severity in the respiratory parameters, but with lower comorbidity percentages. With the current diagnostic criteria, these patients would be excluded from the sleep apnea diagnosis. Conclusions. The application of the strict criterion to detect ‘REM-related OSA’ makes it possible to filter milder forms of sleep apnea associated with percentages of cardiovascular and/or metabolic comorbidity that are not significantly different from other more severe forms of sleep apnea. To avoid under-diagnosis, it would be advisable to review the sleep apnea diagnostic criteria and the indications of the reduced sleep apnea diagnostic techniques (AU)

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

Comorbidity between sleep apnea and insomnia.

The association between insomnia and sleep apnea has received little attention from health professionals in the past few decades. However, recent studies have shown a high prevalence of insomnia complaints in patients with objectively diagnosed obstructive sleep apnea (OSA) syndrome. In this paper we have reviewed data published on different aspects of this association: the clinical profile of sleep-disordered breathing (SDB)-plus, the nature of the association, the role in the onset of insomnia played by OSA itself and other comorbidity factors such as depression or the restless leg syndrome. Finally, we have reviewed data and hypotheses on the metabolic implications of OSA and insomnia, and we speculate on the role that hypothalamic-pituitary-adrenal axis hyperactivity may play in a hypothetical interrelation between OSA and insomnia. The apparent paradox implied by this clinical association reveals the need for interdisciplinary training for physicians who treat both types of disorders.

Síndrome de apnea-hipopnea obstructiva del sueño e insomnio: una asociación frecuente / No disponible

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Trastorno alimentario en relación con el sueño / Sleep related eating disorder

INTRODUCCIÓN. El trastorno alimentario relacionado con el sueño (SRED) se caracteriza por la presencia de arousals nocturnos acompañados de alimentación compulsiva, con nivel de conciencia variable durante los mismos. Con frecuencia el trastorno se acompaña de otras alteraciones del sueño, pero la mayoria de casos publicados no aportan estudios polisomnográficos nocturnos (PSGn). Caso1 Varón de 40 años de edad. Desde los 25 años presenta episodios de levantarse de la cama por la noche para ingerir alimento, recordando el episodio vagamente o sin recordarlo. Refiere antecedentes de sonambulismo personales y familiares. El PSGn muestra la presencia de movimientos periódicos de piernas. Caso 2 Varón de 42 años de edad con historia personal y familiar de sonambulismo. Desde hace varios años presenta episodios de alimentación compulsiva durante la noche que no recuerda al día siguiente. Su PSGn muestra apneas obstructivas relacionadas con la posición del cuerpo. Caso 3 Varón de 40 años con gran cantidad de arousals durante el sueño, durante los que siente la necesidad de comer. Al día siguiente recuerda los episodios. Su PSGn muestra la presencia de escasas apneas. CONCLUSIÓN. El SRED puede estar asociado con otras alteraciones del sueño. Su diagnóstico mediante la ayuda del PSGn y su tratamiento pueden mejorar y hacer que los episodios disminuyan en frecuencia (AU)

INTRODUCTION. Sleep - related eating disorder (SRED) is characterised by arousals from sleep associated with compulsive ingestion of food and subsequent poor memory of the event. SRED is frequently combined with other sleep disorders, but most published reports do not include polysomnografic (PSG) studies. Case 1 Male patient, 40 years old. At age 25 he started getting up every night and eating food with only partial or no recall of the event. He has personal and family history of sleepwalking. His PSG showed the presence of periodic limb movements. Case 2 Male patient, 42 years old with history of sleep walking. Several years ago he started compulsive eating at night without recall of the episode. His PSG showed obstructive sleep apneas related to body position. Case 3 Male patient 40 years old with many arousals from sleep, during which he feels the need to eat. The next day he recalls the episodes. His PSG showed a few obstructive sleep apneas. CONCLUSION. SRED may be associated with other sleep disorders. Their diagnosis by PSG study, and their treatment may improve and decrease the frequency of the events (AU)