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DQB1*0301 and DQB1*0601 Modulate Narcolepsy Susceptibility in Koreans

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DQB1*0301 and DQB1*0601 Modulate Narcolepsy Susceptibility in Koreans DQB1*0301 and DQB1*0601 Modulate Narcolepsy Susceptibility in Koreans Seung-Chul Hong, Ling Lin, Betty Lo, Jong-Hyun Jeong, Yoon-Kyung Shin, Su-Yeon Kim, Yongsil Kweon, Jing Zhang, Mali Einen, Anajane Smith, John Hansen, F. Carl Grumet, and Emmanuel Mignot ABSTRACT: The association of narcolepsy with HLA- DQB1*0602 overabundance and linkage disequilibrium. We DQB1*0602 is established in Japanese, African- therefore next analyzed compound heterozygote effects in 77 Americans, European, and North American Caucasians. We subjects with either hypocretin deficiency or cataplexy and examined DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 one copy of DRB1*1501-DQA1*0102-DQB1*0602, a sam- in 163 patients with centrally mediated daytime sleepiness ple constructed to maximize etiologic homogeneity. In this (100 with narcolepsy) and 211 Korean controls. In this pop- analysis, we found additional predisposing effects of ulation, the DQB1*0602 association was always evident in DQB1*0301 and protective effects for DQA1*0103- the context of the DRB1*1501-DQA1*0102-DQB1*0602 DQB1*0601. Unexpectedly, the predisposing effects of haplotype. The DQB1*0602 association was highest in cases DQB1*0301 were present in the context of various DQA1- with hypocretin deficiency (100% vs 13% in controls), most bearing haplotypes. A predisposing effect of DQA1*0303 of which had narcolepsy-cataplexy (81%). A weaker was also suggested. These results indicate a remarkable con- DQB1*0602 (45%) association was present in cases without sistency in the complex HLA association present in narcolepsy cataplexy. No human leukocyte antigen (HLA) association across multiple ethnic groups. Human Immunology 68, was present in idiopathic hypersomnia or in cases with normal 59–68 (2007). © American Society for Histocompatibility cerebrospinal fluid (CSF) hypocretin-1. As in other popula- and Immunogenetics, 2007. Published by Elsevier Inc. tions, DQB1*0602 homozygosity increased risk in cases with cataplexy and/or hypocretin deficiency (odds ratio ϭ 2.0 vs KEYWORDS: Narcolepsy; cataplexy; hypocretin; orexin; heterozygotes). Non-DQB1*0602 allelic effects were also ob- HLA; DQB1*0602; DQB1*0301; DQB1*0601 served but could not be interpreted in the context of ABBREVIATIONS CSF: cerebrospinal fluid; HLA: human leukocyte antigen INTRODUCTION The sleep disorder narcolepsy is characterized by exces- transitions into rapid eye movement sleep [1, 2]. Recent sive daytime sleepiness, cataplexy (sudden episodes of studies have shown that the human disorder is caused by loss of muscle tone triggered by emotions), and rapid the destruction of most of approximately 70,000 hypo- thalamic neurons that secrete a wake-promoting neu- From the Department of Neuropsychiatry, St. Vincent’s Hospital, The ropeptide called hypocretin (orexin) [3, 4]. Measuring Catholic University of Korea, Suwon, Korea (S.C.H., J.-H.J., Y.-K.S., hypocretin-1 in the cerebrospinal fluid (CSF) of patients S.-Y.K.); Center for Narcolepsy, Stanford University, CA, USA (L.L., is now an accepted diagnostic test, with low levels indi- B.L., J.Z. M.E., E.M.); Stanford Blood Bank, Stanford University, CA, USA (B.L., F.C.G.); Department of Psychiatry, Uijongbu St. Mary’s cating narcolepsy [2, 5, 6]. Based on the observations of Hospital, The Catholic University of Korea, Uijongbu, Korea (Y.K.); and the human leukocyte antigen (HLA) association in the Fred Hutchinson Cancer Research Center, Seattle, WA, USA (A.S., J.H.). Address reprint requests to: Emmanuel Mignot, Center For Narcolepsy, disorder, an autoimmune-mediated destruction of hypo- Stanford University, Department of Psychiatry and Behavioral Sciences, cretin-containing cells has been proposed as the cause of 701B Welch Road, Rm. 143, Palo Alto, CA, 94305; Tel: 650-725- most human cases. In spite intensive research, however, 6517; Fax: 650-725-4913; E-mail: [email protected]. S.-C.H. and L.L. contributed equally to this study. an involvement of the immune system in the pathophys- Received Jul 20, 2006; revised Sep 15, 2006; accepted Oct 2, 2006. iology of the disorder remains unproven [7, 8]. Human Immunology 68, 59–68 (2007) © American Society for Histocompatibility and Immunogenetics, 2007 0198-8859/07/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2006.10.006 60 S.-C. Hong et al. In 1984, Juji et al. first reported a strong association consistent transethnic pattern of association in between HLA-DR2, DQ1, and narcolepsy in Japanese narcolepsy-cataplexy. patients (100% vs 30%) [9]. The DR2 association was rapidly confirmed in Caucasians [10, 11], whereas it was found to be more variable in African-Americans [12]. SUBJECTS AND METHODS Further studies in Caucasians and Japanese have shown Patients that the association is with the DRB1*1501, One hundred sixty-three consecutive patients (2000– DQA1*0102, DQB1*0602 haplotype [13]. More re- 2004) with unexplained sleepiness and 211 controls re- cently, studies in other ethnic groups have shown a cruited at St. Vincent’s Hospital, Korea were included primary effect of DQB1*0602 rather than DRB1*1501. and gave informed consent for the study. The gold In African-Americans, narcolepsy is associated with standard for diagnosis was International Classification of DQB1*0602 haplotypes bearing distinct DRB1 alleles, Sleep Disorders, 2nd edition criteria [2]. Polysomnography most commonly DRB1*1503, DRB1*1501, DRB1* (87%), a multiple sleep latency test (96%), and CSF 1101, and DRB1*0806 [14, 15]. hypocretin-1 measurements (53%) were conducted in Interestingly, the association with DQB1*0602 is patients to further confirm the diagnosis. Patients were extremely strong only in subjects with typical cataplexy separated into diagnostic groupings based on the Inter- [16, 17], most of which also have low CSF hypocretin national Classification of Sleep Disorders, 2nd edition. [2]. [13]. The DQB1*0602 association is decreased or absent This categorization resulted in the following groupings: in subjects without cataplexy. Additionally, less than 1% (1) narcolepsy with cataplexy (presence of cataplexy trig- of subjects with low hypocretin levels and cataplexy are gered by strong emotions, most typically joking and DQB1*0602 negative [13]. These findings suggest dis- laughing), (2) narcolepsy without cataplexy (no or atyp- ease heterogeneity or partial hypocretin deficiency that is ical cataplexy but multiple rapid eye movement sleep not reflected by decreased CSF levels in HLA- transitions during the multiple sleep latency test), and DQB1*0602–negative subjects and patients without (3) idiopathic hypersomnia cases (unexplained sleepiness cataplexy [13]. without multiple transitions into rapid eye movement Effects more complex than a simple dominant effect of sleep during the multiple sleep latency test). Detailed DQB1*0602 on narcolepsy susceptibility can also be clinical evaluation for these patients has been published detected and are still under investigation. A twofold to elsewhere [26]. We also constructed a sample of 83 likely fourfold increased risk in DQB1*0602 homozygous ver- hypocretin-deficient patients, as described in Figure 1. sus heterozygotes has been demonstrated in Japanese, The sample included all subjects with documented low- Caucasians, and African-Americans in case-control sam- CSF hypocretin-1 (n ϭ 55, all DQB1*0602 positive) and ples [18, 19]. Additional susceptibility effects have also subjects with typical cataplexy and DQB1*0602 (n ϭ been detected in selected DQB1*0301/X heterozygotes. 28). Based on previous observations and DQB1*0602 Most notably, DQB1*0602/DQB1*0301 heterozygotes frequency in the Korean population, this sample is likely are at increased risk, whereas decreased susceptibility is to contain only subjects with hypocretin deficiency. observed in DQB1*0602/DQB1*0601 and DQB1* 0602/DQB1*0501 heterozygotes [19]. These findings HLA-DR and DQ Typing have been replicated using a conditional transmission All samples were HLA-DRB and DQB1-typed at Stan- disequilibrium test trio family study in the context of the ford University using sequence specific amplification 13th International Histocompatibility Workshop [20]. followed by allele sequencing using an Applied Biosys- A possible additional effect of DRB1*0407 on tem capillary sequencer (Applied Biosystems, Foster DRB1*0407-DQB1*0301 was also observed for the first City, CA USA). High-level typing resolution for DRB1 time in this later study [20]. and DQB1 was obtained in all cases. DQA1 typing was Much has been learned in the HLA field through performed at the Fred Hutchinson Cancer Research Cen- transethnic association studies [19–25]. In this study, we ter, Seattle, using a reverse probe format sequence spe- extended our HLA analysis to a large sample of Korean cific oligonucleotide probes (SSOP) typing system Inno- narcolepsy patients. Well-characterized patients with genetics line probe assay (INNO-LIPA) HLA-DQA1, classical narcolepsy-cataplexy, without cataplexy, and Innogenetics, Belgium). The INNO-LIPA reagents em- with other related disorders of excessive daytime sleepi- ploy multiplex amplification of exons 1, 2, and 3. Thir- ness were studied [26]. The study was also extended to ty-five probes to polymorphisms distinguishing all of the include DRB1, DRB3, DRB4, DRB5, DQA1, and known HLA-DQA1 alleles were bound on nylon mem- DQB1 typing. The results suggest DQB1*0301 effects brane strips. Hybridization and detection were per- independent of DQA1, and they reveal a remarkably formed with the Auto-LiPA 48 machine and analysis
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