title: A polymorphism in CCR1/CCR3 is associated with narcolepsy.
abstract: Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Toyoda
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: miyagawa-taku@umin.ac.jp.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Research & Development Group, Hitachi, Ltd., Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Koike
authors.affiliation: Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanbayashi
authors.affiliation: Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Imanishi
authors.affiliation: Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sagawa
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan; Kotorii Isahaya Hospital, Nagasaki, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kotorii
authors.affiliation: Kotorii Isahaya Hospital, Nagasaki, Japan.
authors.forename: Tatayu
authors.initials: T
authors.lastname: Kotorii
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hashizume
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Ogi
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiejima
authors.affiliation: Sleep Disorder Center, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kamei
authors.affiliation: Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hida
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Imai
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Yota
authors.initials: Y
authors.lastname: Fujimura
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Sleep Center, Kuwamizu Hospital, Kumamoto, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Ikegami
authors.affiliation: Department of Psychiatry, Hannan Hospital, Osaka, Japan.
authors.forename: Yamato
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.
authors.forename: Shunpei
authors.initials: S
authors.lastname: Moriya
authors.affiliation: Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.affiliation: Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan; Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kirino
authors.affiliation: Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.affiliation: Department of Psychiatry, Sakae Seijinkai Hospital, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otowa
authors.affiliation: Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Seik-Soon
authors.initials: SS
authors.lastname: Khor
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Maria
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.affiliation: Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishigooka
authors.affiliation: Department of Psychiatry, Hannan Hospital, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Sleep Center, Kuwamizu Hospital, Kumamoto, Japan; Department of Stem Cell Biology, Institute of Molecular Genetics and Embryology, Kumamoto University, Kumamoto, Japan; Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Sleep Medicine, Shiga University of Medical Science, Shiga, Japan; Japan Foundation for Neuroscience and Mental Health, Tokyo, Japan; Department of Somnology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Okawa
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Mizuki
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Uchimura
authors.affiliation: Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan; Department of Somnology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan; Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
mesh_terms: D044466:Asian People; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D009290:Narcolepsy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054389:Receptors, CCR1 / Q000235:genetics*; D054397:Receptors, CCR3 / Q000235:genetics*
chemical_list: C515300:CCR1 protein, human; C515350:CCR3 protein, human; D054389:Receptors, CCR1; D054397:Receptors, CCR3
keywords: Chemokine receptor; Complex traits; Genome-wide association study; Microglia; Narcolepsy; Neuroinflammation