Narcolepsy is strongly associated with the T-cell receptor alpha locus

被引：341

作者：

Hallmayer, Joachim ^{[1
,2
]}

Faraco, Juliette ^{[1
,2
]}

Lin, Ling ^{[1
,2
]}

Hesselson, Stephanie ^{[3
]}

Winkelmann, Juliane ^{[4
,5
,6
]}

Kawashima, Minae ^{[1
,2
,7
]}

Mayer, Geert ^{[8
,9
]}

Plazzi, Giuseppe ^{[10
]}

Nevsimalova, Sona ^{[11
,12
]}

Bourgin, Patrice ^{[13
]}

Hong, Sheng Seung-Chul ^{[14
]}

Honda, Yutaka ^{[15
]}

Honda, Makoto ^{[15
]}

Hoegl, Birgit ^{[16
]}

Longstreth, William T., Jr. ^{[17
,18
]}

Montplaisir, Jacques ^{[19
]}

Kemlink, David ^{[11
,12
]}

Einen, Mali ^{[1
,2
]}

Chen, Justin ^{[3
]}

Musone, Stacy L. ^{[3
]}

Akana, Matthew ^{[3
]}

Miyagawa, Taku ^{[7
]}

Duan, Jubao ^{[20
]}

Desautels, Alex ^{[19
]}

Erhardt, Christine ^{[13
]}

Hesla, Per Egil ^{[21
]}

Poli, Francesca ^{[10
]}

Frauscher, Birgit ^{[16
]}

Jeong, Jong-Hyun ^{[14
]}

Lee, Sung-Pil ^{[14
]}

Ton, Thanh G. N. ^{[17
,18
]}

Kvale, Mark ^{[3
]}

Kolesar, Libor ^{[22
]}

Dobrovolna, Marie ^{[23
]}

Nepom, Gerald T. ^{[24
]}

Salomon, Dan ^{[25
]}

Wichmann, H-Erich ^{[26
,27
]}

Rouleau, Guy A. ^{[28
]}

Gieger, Christian ^{[26
]}

Levinson, Douglas F. ^{[2
]}

Gejman, Pablo V. ^{[20
,29
]}

Meitinger, Thomas ^{[4
,6
]}

Young, Terry ^{[30
]}

Peppard, Paul ^{[30
]}

Tokunaga, Katsushi ^{[7
]}

Kwok, Pui-Yan ^{[3
]}

Risch, Neil ^{[3
,31
]}

Mignot, Emmanuel ^{[1
,2
,32
]}

机构：

[1] Stanford Univ, Sch Med, Ctr Sleep Sci, Palo Alto, CA 94304 USA

[2] Stanford Univ, Sch Med, Dept Psychiat, Palo Alto, CA 94304 USA

[3] Univ Calif San Francisco, Sch Med, Inst Human Genet, San Francisco, CA USA

[4] Tech Univ Munich, Inst Human Genet, Munich, Germany

[5] Tech Univ Munich, Dept Neurol, Munich, Germany

[6] Helmholtz Zentrum Munchen, Inst Human Genet, Munich, Germany

[7] Univ Tokyo, Dept Human Genet, Tokyo, Japan

[8] Hephata Klin, Schwalmstadt, Germany

[9] Univ Marburg, Dept Neurol, Marburg, Germany

[10] Univ Bologna, Bologna, Italy

[11] Charles Univ Prague, Fac Med 1, Dept Neurol, Prague, Czech Republic

[12] Gen Teaching Hosp, Prague, Czech Republic

[13] Univ Strasbourg, Hop Civil, Sleep Clin, Strasbourg, France

[14] Catholic Univ Korea, St Vincents Hosp, Dept Neuropsychiat, Suwon, South Korea

[15] Tokyo Inst Psychiat, Tokyo, Japan

[16] Innsbruck Med Univ, Dept Neurol, Innsbruck, Austria

[17] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[18] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[19] Univ Montreal, Sleep Disorders Ctr, Montreal, PQ, Canada

[20] Northwestern Univ, Feinberg Sch Med, Dept Psychiat, Evanston, IL USA

[21] Coliseum Majorstua Clin, Oslo, Norway

[22] Inst Clin & Expt Med, Dept Immunogenet, Prague, Czech Republic

[23] Inst Hematol & Blood Transfus, Natl Reference Lab DNA Diagnost, HLA Typing Lab, CR-12820 Prague, Czech Republic

[24] Benaroya Res Inst Virginia Mason, Seattle, WA USA

[25] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

[26] Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany

[27] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[28] Univ Montreal, Ctr Excellence Neur, Montreal, PQ, Canada

[29] N Shore Univ HlthSyts, Evanston, IL USA

[30] Univ Wisconsin, Sch Med, Dept Populat Hlth Sci, Madison, WI USA

[31] Kaiser Permanente No Calif Div Res, Oakland, CA USA

[32] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 06期

关键词：

GENOME-WIDE ASSOCIATION; INFORMATION; EVOLUTION; MUTATION; REGION; GENE;

D O I：

10.1038/ng.372

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals(1,2). Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs(5) and mice(6), a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported(7,8). Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders(9); thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders(9).

引用

页码：708 / 711

页数：4

共 25 条

[1] Narcolepsy in orexin knockout mice:: Molecular genetics of sleep regulation [J].

Chemelli, RM ;

Willie, JT ;

Sinton, CM ;

Elmquist, JK ;

Scammell, T ;

Lee, C ;

Richardson, JA ;

Williams, SC ;

Xiong, YM ;

Kisanuki, Y ;

Fitch, TE ;

Nakazato, M ;

Hammer, RE ;

Saper, CB ;

Yanagisawa, M .

CELL, 1999, 98 (04) :437-451

[2] A second generation human haplotype map of over 3.1 million SNPs [J].

Frazer, Kelly A. ;

Ballinger, Dennis G. ;

Cox, David R. ;

Hinds, David A. ;

Stuve, Laura L. ;

Gibbs, Richard A. ;

Belmont, John W. ;

Boudreau, Andrew ;

Hardenbol, Paul ;

Leal, Suzanne M. ;

Pasternak, Shiran ;

Wheeler, David A. ;

Willis, Thomas D. ;

Yu, Fuli ;

Yang, Huanming ;

Zeng, Changqing ;

Gao, Yang ;

Hu, Haoran ;

Hu, Weitao ;

Li, Chaohua ;

Lin, Wei ;

Liu, Siqi ;

Pan, Hao ;

Tang, Xiaoli ;

Wang, Jian ;

Wang, Wei ;

Yu, Jun ;

Zhang, Bo ;

Zhang, Qingrun ;

Zhao, Hongbin ;

Zhao, Hui ;

Zhou, Jun ;

Gabriel, Stacey B. ;

Barry, Rachel ;

Blumenstiel, Brendan ;

Camargo, Amy ;

Defelice, Matthew ;

Faggart, Maura ;

Goyette, Mary ;

Gupta, Supriya ;

Moore, Jamie ;

Nguyen, Huy ;

Onofrio, Robert C. ;

Parkin, Melissa ;

Roy, Jessica ;

Stahl, Erich ;

Winchester, Ellen ;

Ziaugra, Liuda ;

Altshuler, David ;

Shen, Yan .

NATURE, 2007, 449 (7164) :851-U3

[3] Analysis of the TCR α-chain rearrangement profile in human T lymphocytes [J].

Fuschiotti, Patrizia ;

Pasqual, Nicolas ;

Hierle, Vivien ;

Borel, Eve ;

London, Jacqueline ;

Marche, Patrice Noel ;

Jouvin-Marche, Evelyne .

MOLECULAR IMMUNOLOGY, 2007, 44 (13) :3380-3388

[4] T-cell receptor peptide-MHC interactions: biological lessons from structural studies [J].

Garcia, KC ;

Teyton, L .

CURRENT OPINION IN BIOTECHNOLOGY, 1998, 9 (04) :338-343

[5] Evolution of the variable gene segments and recombination signal sequences of the human T-cell receptor α/δ locus [J].

Haynes, MR ;

Wu, GE .

IMMUNOGENETICS, 2004, 56 (07) :470-479

[6] HLA ANTIGENS IN JAPANESE PATIENTS WITH NARCOLEPSY - ALL THE PATIENTS WERE DR2 POSITIVE [J].

JUJI, T ;

SATAKE, M ;

HONDA, Y ;

DOI, Y .

TISSUE ANTIGENS, 1984, 24 (05) :316-319

[7] THE HUMAN T-CELL RECEPTOR TCRAC/TCRDC (C-ALPHA/C-DELTA) REGION - ORGANIZATION, SEQUENCE, AND EVOLUTION OF 97.6 KB OF DNA [J].

KOOP, BF ;

ROWEN, L ;

WANG, K ;

KUO, CL ;

SETO, D ;

LENSTRA, JA ;

HOWARD, S ;

SHAN, W ;

DESHPANDE, P ;

HOOD, L .

GENOMICS, 1994, 19 (03) :478-493

[8] IMGT®, the international ImMunoGeneTics information system® [J].

Lefranc, Marie-Paule ;

Giudicelli, Veronique ;

Ginestoux, Chantal ;

Jabado-Michaloud, Joumana ;

Folch, Geraldine ;

Bellahcene, Fatena ;

Wu, Yan ;

Gemrot, Elodie ;

Brochet, Xavier ;

Lane, Jerome ;

Regnier, Laetitia ;

Ehrenmann, Francois ;

Lefranc, Gerard ;

Duroux, Patrice .

NUCLEIC ACIDS RESEARCH, 2009, 37 :D1006-D1012

[9] Autoimmune diseases: insights from genome-wide association studies [J].

Lettre, Guillaume ;

Rioux, John D. .

HUMAN MOLECULAR GENETICS, 2008, 17 :R116-R121

[10] The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene [J].

Lin, L ;

Faraco, J ;

Li, R ;

Kadotani, H ;

Rogers, W ;

Lin, XY ;

Qiu, XH ;

de Jong, PJ ;

Nishino, S ;

Mignot, E .

CELL, 1999, 98 (03) :365-376

← 1 2 3 →