A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan

Ahmed, Wael A.; Tsutsumi, Makiko; Nakata, Seiichi; Mori, Terumi; Nishimura, Yoichi; Fujisawa, Toshiyuki; Kato, Ichiro; Nakashima, Mayuki; Kurahashi, Hiroki; Suzuki, Kenji

doi:10.1002/lary.23179

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…Abnormalities in orexin signaling pathways underlie the pathophysiology of sleep disorders (Baumann and Bassetti, 2005a, b; Cao and Guilleminault, 2011; Dyken and Yamada, 2005; Malhotra and Kushida, 2013; Mignot, 2004; Overeem et al, 2001; Ritchie et al, 2010; Tafti et al, 2005; Taheri et al, 2002; Wisor and Kilduff, 2005; Zeitzer, 2013) such as narcolepsy (Nishino et al, 2000; Peyron et al, 2000; Thannickal et al, 2000) and may contribute to posttraumatic hypersomnia or excessive daytime sleepiness due to traumatic brain injury (Baumann, 2012; Baumann et al, 2009), post traumatic stress disorder (Strawn et al, 2010), or obstructive sleep apnea (Ahmed et al, 2012; Wang et al, 2013). Insufficient central orexin signaling has also been associated with other medical conditions (Mignot et al, 2002; Vankova et al, 2003) such as obesity (Van Cauter and Knutson, 2008), age-related anorexia (Kmiec et al, 2013), multiple system atrophy (Benarroch et al, 2007), neurological disorders (Fronczek et al, 2009), Parkinson’s disease (Fronczek et al, 2007; Thannickal et al, 2007; Wienecke et al, 2012), and Alzheimer’s disease (Slats et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Sleep disorders, obesity, and aging: The role of orexin

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

112

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The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.

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Section: Discussionmentioning

confidence: 99%

Sleep disorders, obesity, and aging: The role of orexin

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

112

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“…Based on our results, it seems reasonable to speculate that HCRT variants are not involved in the development of OSAHS. The previous study reported that circulating hypocretin levels were significantly lower in OSAHS patients than controls, and inversely correlated with the severity of OSAHS [ 19 , 20 ]; however, a clinical trial by Ahmed et al [ 8 ] had previously found that the frequency of the HCRT rs9902709 variation increased HCRT expression, and was associated with a decreased risk for OSAHS in the Japanese population. These differences between the two studies may be primarily attributed to environmental factors which have the potential to interact with the genetic background.…”

Section: Discussionmentioning

confidence: 99%

“…An association between Ala20Val polymorphism and C/C variant of the GABBR1 Phe658Phe polymorphism and OSAHS had been reported in Turkish individuals [ 6 ], but not for the genotype and allele frequencies of IRS-1 rs1801278 [ 7 ]. In addition, also, an association between the C allele of the HCRT rs9902709 variation and OSAHS was reported in a Japanese population [ 8 ]. Hence based on these findings the objective of this study was to investigate genotype-phenotype changes between rs29230 in γ-aminobutyric acid B receptor (GABBR1) , rs1801278 in insulin receptor substrate-1 (IRS-1) , rs9902709 in hypocretin neuropeptide precursor (HCRT) and OSAHS in Chinese Han individuals.…”

Section: Introductionmentioning

confidence: 99%

Association between Single Nucleotide Polymorphisms in Gamma-Aminobutyric Acid B Receptor, Insulin Receptor Substrate-1, and Hypocretin Neuropeptide Precursor Genes and Susceptibility to Obstructive Sleep Apnea Hypopnea Syndrome in a Chinese Han Population

Tang²,

Du³

et al. 2016

Med Princ Pract

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Objective: To investigate genotype-phenotype changes between rs29230 in γ-aminobutyric acid B receptor (GABBR1), rs1801278 in insulin receptor substrate-1 (IRS-1), and rs9902709 in hypocretin neuropeptide precursor (HCRT) and obstructive sleep apnea hypopnea syndrome (OSAHS) in Chinese Han individuals. Materials and Methods: A total of 130 patients with OSAHS and 136 age- and gender-matched healthy controls were enrolled in this study. A brief description of DNA extraction and genotyping is given. Multivariate unconditional logistic regression analysis adjusted for gender and age was used to estimate the associations of single nucleotide polymorphisms (SNPs) rs29230 (GABBR1), rs1801278 (IRS-1), and rs9902709 (HCRT) with OSAHS risk. Subgroup analysis was performed to evaluate differences in these SNPs among subgroups according to gender, body mass index (BMI), and severity of disease. Results: Genotype and allele frequencies of rs29230 were significantly different between cases and controls (p = 0.0205 and p = 0.0191, respectively; odds ratio = 0.493, 95% confidence interval = 0.271-0.896), especially for male patients (p = 0.0259 and p = 0.0202, respectively). Subgroup analysis according to BMI also revealed a significant allele difference for rs29230 between cases and controls in the overweight subgroup (p = 0.0333). Furthermore, allele and genotype frequencies of rs1801278 showed significant differences between cases and controls (p = 0.0488 and p = 0.0471, respectively). However, no association was observed between rs9902709 and OSAHS risk (p = 0.2762), and no differences were identified in other subgroups. Conclusion: In this study, there was an association between variants of rs29230 and rs1801278 and OSAHS risk in the Chinese Han population but not for rs9902709.

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“…However, gene association studies also reveal a significant relationship between the genetic predisposition for narcolepsy-cataplexy and OSA. Specifically, a distinct polymorphism of the preproorexin gene has been associated with OSA (5, 89). It is possible that subtle metabolic consequences of orexin deficiency contribute to the link between OSA and narcolepsy.…”

Section: Neural Control Of the Upper Airway In Sleep-disordered Breatmentioning

confidence: 99%

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Kubin

2016

Comprehensive Physiology

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Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA.

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A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan

Abstract: Our genetic association study, followed by functional and quantitative phenotyping assays, demonstrated a functional locus within the HCRT gene, which may act to increase HCRT expression and lead to a protective effect against the development of OSAS.

Cited by 9 publications

References 23 publications

Sleep disorders, obesity, and aging: The role of orexin

Sleep disorders, obesity, and aging: The role of orexin

Association between Single Nucleotide Polymorphisms in Gamma-Aminobutyric Acid B Receptor, Insulin Receptor Substrate-1, and Hypocretin Neuropeptide Precursor Genes and Susceptibility to Obstructive Sleep Apnea Hypopnea Syndrome in a Chinese Han Population

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

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