A polymorphism in CCR1/CCR3 is associated with narcolepsy

作者：Toyoda Hiromi; Miyagawa Taku^*; Koike Asako; Kanbayashi Takashi; Imanishi Aya; Sagawa Yohei; Kotorii Nozomu; Kotorii Tatayu; Hashizume Yuji; Ogi Kimihiro; Hiejima Hiroshi; Kamei Yuichi; Hida Akiko; Miyamoto Masayuki; Imai Makoto; Fujimura Yota; Tamura Yoshiyuki; Ikegami Azusa; Wada Yamato; Moriya Shunpei; Furuya Hirokazu; Takeuchi Masaki; Kirino Yohei; Meguro Akira; Remmers Elaine F; Kawamura Yoshiya; Otowa Takeshi; Miyashita Akinori; Kashiwase Koichi

来源：Brain, Behavior, and Immunity, 2015, 49: 148-155.

DOI：10.1016/j.bbi.2015.05.003

• Narcolepsy
• Chemokine receptor
• Neuroinflammation
• Genome-wide association study
• Complex traits
• Microglia

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 x 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.

• 出版日期2015-10
• 单位河北医科大学