Miyagawa Taku, Toyoda Hiromi, Hirataka Akane, 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, Kato Mitsuhiro, Omata Naoto, Kojima Hiroto, Kashiwase Koichi, Saji Hiroh, Khor Seik-Soon, Yamasaki Maria, Wada Yuji, Ishigooka Jun, Kuroda Kenji, Kume Kazuhiko, Chiba Shigeru, Yamada Naoto, Okawa Masako, Hirata Koichi, Uchimura Naohisa, Shimizu Tetsuo, Inoue Yuichi, Honda Yutaka, Mishima Kazuo, Honda Makoto, Tokunaga Katsushi
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hum Mol Genet. 2015 Feb 1;24(3):891-8. doi: 10.1093/hmg/ddu480. Epub 2014 Sep 25.
Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB106:02. DQB106:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB106:02 are associated with narcolepsy. The strongest association was with DQB106:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB103:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB106:02 heterozygous cases and controls revealed dominant protective effects of DQB106:01 and DQB105:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.
发作性睡病是一种以白天过度嗜睡、猝倒和快速眼动睡眠异常为特征的睡眠障碍，与人类白细胞抗原HLA - DQB106:02密切相关。DQB106:02在普通人群中很常见（10 - 30%）；因此，发作性睡病的发生还需要其他遗传因素。在本研究中，对664名日本发作性睡病患者和3131名日本对照者的HLA - DQB1进行了检测，以确定位于DQB106:02反式位置的HLA - DQB1等位基因是否与发作性睡病相关。如先前研究报道，最强的关联是与DQB106:01（P = 1.4×10⁻¹⁰，优势比，OR = 0.39）。还发现了DQB103:02的额外易患效应（P = 2.5×10⁻⁹，OR = 1.97）。对DQB106:02杂合病例和对照的比较显示了DQB106:01和DQB105:01的显性保护作用。此外，进行了基于单核苷酸多态性的条件分析，以控制HLA - DQB1的效应，从而确定在HLA - DQB1之外是否存在其他独立的HLA关联。该分析揭示了HLA II类区域中HLA - DPB1的关联（rs3117242，P = 4.1×10⁻⁵，OR = 2.45；DPB1*05:01，P = 8.1×10⁻³，OR = 1.39）。这些结果表明，复杂的HLA II类关联促成了发作性睡病的遗传易感性。
