New susceptibility variants to narcolepsy identified in HLA class II region

• Published in: Human molecular genetics Vol. 24; no. 3; pp. 891 - 898
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 01.02.2015
• Subjects: Asian Continental Ancestry Group - genetics; Genes, MHC Class II; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; HLA-DP beta-Chains - genetics; HLA-DQ beta-Chains - genetics; Humans; Japan; Narcolepsy - genetics; Japan
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddu480

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.