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

Authors

  • Wael A. Ahmed MD, PhD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
    2. Department of Otolaryngology, Sohag Faculty of Medicine, Sohag University, Egypt
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  • Makiko Tsutsumi PhD,

    1. Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
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  • Seiichi Nakata MD, PhD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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  • Terumi Mori MSc,

    1. 21st Century COE Program, Development Center for Targeted and Minimally Invasive Diagnosis and Treatment, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
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  • Yoichi Nishimura MD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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  • Toshiyuki Fujisawa MD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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  • Ichiro Kato MD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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  • Mayuki Nakashima MD, PhD,

    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
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  • Hiroki Kurahashi MD, PhD,

    1. Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
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  • Kenji Suzuki MD, PhD

    Corresponding author
    1. Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
    • Department of Otolaryngology, Second Hospital, School of Medicine, Fujita Health University, 3-6-10, Otobashi, Nakagawa Ku, Nagoya, Aichi, 454-8509, Japan
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  • This study was supported by a grant-in-aid for the 21st Century Center of Excellence Program of Fujita Health University from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The study was also supported in part by a grant from the Society for Promotion of International Oto-Rhino-Laryngology, Japan. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Abstract

Objectives/Hypothesis:

To evaluate the association of hypocretin neuropeptide precursor gene (HCRT) variations with obstructive sleep apnea syndrome (OSAS) in a cohort of Japanese patients and to further evaluate whether the significant HCRT variations have potential functional consequences on HCRT expression.

Study Design:

Case-control genetic association study.

Methods:

We studied the genetic variations within the HCRT gene. The study population consisted of 100 OSAS patients and 100 control subjects. The HCRT gene was amplified by polymerase chain reaction in all study subjects followed by direct sequencing and analysis of sequencing data.

Results:

Two genetic variations within the HCRT intron, IVS1+16T>C (rs9902709) and IVS1−69G>C, were identified with significant differences between patients and controls (P < .05). A reporter gene assay using HeLa cells showed that the construct containing the C allele of the rs9902709 variation had significantly higher luciferase activity compared with the construct containing the T allele (P = .002). Furthermore, enzyme immunoassay revealed that subjects with T/C and C/C genotypes for rs9902709 had 1.4-fold and 1.5-fold increases in sera levels of orexin-A, respectively.

Conclusions:

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. Laryngoscope, 2012

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