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New susceptibility variants to narcolepsy identified in HLA class II region

2014; Oxford University Press; Volume: 24; Issue: 3 Linguagem: Inglês

10.1093/hmg/ddu480

1460-2083

Taku Miyagawa, Hiromi Toyoda, Akane Hirataka, 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, Mitsuhiro Kato, Naoto Omata, Hiroto Kojima, Koichi Kashiwase, Hiroh Saji, Seik‐Soon Khor, Maria Yamasaki, Yuji Wada, Jun Ishigooka, Kenji Kuroda, Kazuhiko Kume, Shigeru Chiba, Naoto Yamada, Masako Okawa, Koichi Hirata, Naohisa Uchimura, Tetsuo Shimizu, Yuichi Inoue, Yutaka Honda, Kazuo Mishima, Makoto Honda, Katsushi Tokunaga,

Regulation of Appetite and Obesity

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 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 DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10−10, odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10−9, OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. 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.