A polymorphism in CCR1/CCR3 is associated with narcolepsy

Hiromi Toyoda; Taku Miyagawa; Asako Koike; Takashi Kanbayashi; Aya Imanishi; Yohei Sagawa; Nozomu Kotorii; Tatayu Kotorii; Yuji Hashizume; Kimihiro Ogi; Hiroshi Hiejima; Yuichi Kamei; Akiko Hida; Masayuki Miyamoto; Makoto Imai; Yota Fujimura; Yoshiyuki Tamura; Azusa Ikegami; Yamato Wada; Shunpei Moriya; Hirokazu Furuya; Masaki Takeuchi; Yohei Kirino; Akira Meguro; Elaine F Remmers; Yoshiya Kawamura; Takeshi Otowa; Akinori Miyashita; Koichi Kashiwase; Seik-Soon Khor; Maria Yamasaki; Ryozo Kuwano; Tsukasa Sasaki; Jun Ishigooka; Kenji Kuroda; Kazuhiko Kume; Shigeru Chiba; Naoto Yamada; Masako Okawa; Koichi Hirata; Nobuhisa Mizuki; Naohisa Uchimura; Tetsuo Shimizu; Yuichi Inoue; Yutaka Honda; Kazuo Mishima; Makoto Honda; Katsushi Tokunaga

doi:10.1016/j.bbi.2015.05.003

A polymorphism in CCR1/CCR3 is associated with narcolepsy

Brain Behav Immun. 2015 Oct:49:148-55. doi: 10.1016/j.bbi.2015.05.003. Epub 2015 May 15.

Authors

Hiromi Toyoda¹, Taku Miyagawa², Asako Koike³, Takashi Kanbayashi⁴, Aya Imanishi⁴, Yohei Sagawa⁴, Nozomu Kotorii⁵, Tatayu Kotorii⁶, Yuji Hashizume⁷, Kimihiro Ogi⁷, Hiroshi Hiejima⁷, Yuichi Kamei⁸, Akiko Hida⁹, Masayuki Miyamoto¹⁰, Makoto Imai¹¹, Yota Fujimura¹², Yoshiyuki Tamura¹², Azusa Ikegami¹³, Yamato Wada¹⁴, Shunpei Moriya¹⁵, Hirokazu Furuya¹⁶, Masaki Takeuchi¹⁷, Yohei Kirino¹⁸, Akira Meguro¹⁹, Elaine F Remmers²⁰, Yoshiya Kawamura²¹, Takeshi Otowa²², Akinori Miyashita²³, Koichi Kashiwase²⁴, Seik-Soon Khor¹, Maria Yamasaki¹, Ryozo Kuwano²³, Tsukasa Sasaki²⁵, Jun Ishigooka¹⁵, Kenji Kuroda¹⁴, Kazuhiko Kume²⁶, Shigeru Chiba¹², Naoto Yamada¹¹, Masako Okawa²⁷, Koichi Hirata¹⁰, Nobuhisa Mizuki¹⁹, Naohisa Uchimura⁷, Tetsuo Shimizu⁴, Yuichi Inoue²⁸, Yutaka Honda²⁹, Kazuo Mishima⁹, Makoto Honda³⁰, Katsushi Tokunaga¹

Affiliations

¹ Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: miyagawa-taku@umin.ac.jp.
³ Research & Development Group, Hitachi, Ltd., Japan.
⁴ Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan.
⁵ Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan; Kotorii Isahaya Hospital, Nagasaki, Japan.
⁶ Kotorii Isahaya Hospital, Nagasaki, Japan.
⁷ Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
⁸ Sleep Disorder Center, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁹ Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁰ Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
¹¹ Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan.
¹² Department of Psychiatry and Neurology, Asahikawa Medical University, Hokkaido, Japan.
¹³ Sleep Center, Kuwamizu Hospital, Kumamoto, Japan.
¹⁴ Department of Psychiatry, Hannan Hospital, Osaka, Japan.
¹⁵ Department of Psychiatry, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.
¹⁶ Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.
¹⁷ 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.
¹⁸ 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.
¹⁹ Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
²⁰ Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²¹ Department of Psychiatry, Sakae Seijinkai Hospital, Kanagawa, Japan.
²² Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²³ Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
²⁴ Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
²⁵ Laboratory of Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
²⁶ 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.
²⁷ 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.
²⁸ Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan; Department of Somnology, Tokyo Medical University, Tokyo, Japan.
²⁹ Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
³⁰ 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.

PMID: 25986216
DOI: 10.1016/j.bbi.2015.05.003

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.

Keywords: Chemokine receptor; Complex traits; Genome-wide association study; Microglia; Narcolepsy; Neuroinflammation.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Asian People
Genome-Wide Association Study
Humans
Japan
Narcolepsy / genetics*
Polymorphism, Single Nucleotide*
Receptors, CCR1 / genetics*
Receptors, CCR3 / genetics*

Substances

CCR1 protein, human
CCR3 protein, human
Receptors, CCR1
Receptors, CCR3

Grants and funding

Intramural NIH HHS/United States