A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility

被引：223

作者：

Kochi, Yuta ^{[1
]}

Okada, Yukinori ^{[2
,3
]}

Suzuki, Akari ^{[1
]}

Ikari, Katsunori ^{[4
]}

Terao, Chikashi ^{[5
]}

Takahashi, Atsushi ^{[2
]}

Yamazaki, Keiko ^{[6
]}

Hosono, Naoya ^{[6
]}

Myouzen, Keiko ^{[1
]}

Tsunoda, Tatsuhiko ^{[7
]}

Kamatani, Naoyuki ^{[2
]}

Furuichi, Tatsuya ^{[8
]}

Ikegawa, Shiro ^{[8
]}

Ohmura, Koichiro ^{[5
]}

Mimori, Tsuneyo ^{[5
]}

Matsuda, Fumihiko ^{[9
]}

Iwamoto, Takuji ^{[4
]}

Momohara, Shigeki ^{[4
]}

Yamanaka, Hisashi ^{[4
]}

Yamada, Ryo ^{[1
,9
]}

Kubo, Michiaki ^{[6
]}

Nakamura, Yusuke ^{[10
,11
]}

Yamamoto, Kazuhiko ^{[1
,3
]}

机构：

[1] RIKEN, CGM, Lab Autoimmune Dis, Yokohama, Kanagawa, Japan

[2] RIKEN, CGM, Lab Stat Anal, Yokohama, Kanagawa, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo, Japan

[4] Tokyo Womens Med Univ, Inst Rheumatol, Tokyo, Japan

[5] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin Immunol, Kyoto, Japan

[6] RIKEN, CGM, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[7] RIKEN, CGM, Lab Med Informat, Yokohama, Kanagawa, Japan

[8] RIKEN, CGM, Lab Bone & Joint Dis, Yokohama, Kanagawa, Japan

[9] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[10] RIKEN, CGM, Lab Int Alliance, Yokohama, Kanagawa, Japan

[11] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Mol Med Lab, Tokyo, Japan

来源：

NATURE GENETICS | 2010年 / 42卷 / 06期

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; EFFECTOR T-CELLS; JAPANESE POPULATION; TH17; CELLS; CROHNS-DISEASE; RISK LOCUS; POLYMORPHISM; RECRUITMENT; TRAF1-C5;

D O I：

10.1038/ng.583

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here, through a genome-wide association study of rheumatoid arthritis, we identified a polymorphism in CCR6, the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells) at 6q27, that was associated with rheumatoid arthritis susceptibility and was validated in two independent replication cohorts from Japan (rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, P = 7.7 x 10(-19)). We identified a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with the expression level of CCR6 and was associated with the presence of interleukin-17 (IL-17) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves' and Crohn's diseases. These results suggest that CCR6 is critically involved in IL-17-driven autoimmunity in human diseases.

引用

页码：515 / U63

页数：7

共 42 条

[1] An anti-rheumatic agent T-614 inhibits NF-κB activation in LPS- and TNF-α-stimulated THP-1 cells without interfering with 1κBα degradation [J].

Aikawa, Y ;

Yamamoto, M ;

Yamamoto, T ;

Morimoto, K ;

Tanaka, K .

INFLAMMATION RESEARCH, 2002, 51 (04) :188-194

[2] Phenotypic and functional features of human Th17 cells [J].

Annunziato, Francesco ;

Cosmi, Lorenzo ;

Santarlasci, Veronica ;

Maggi, Laura ;

Liotta, Francesco ;

Mazzinghi, Benedetta ;

Parente, Eliana ;

Fili, Lucia ;

Ferri, Simona ;

Frosali, Francesca ;

Giudici, Francesco ;

Romagnani, Paola ;

Parronchi, Paola ;

Tonelli, Francesco ;

Maggi, Enrico ;

Romagnani, Sergio .

JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (08) :1849-1861

[3] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[4] Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease [J].

Brand, S. .

GUT, 2009, 58 (08) :1152-1167

[5] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[6] Genomic control, a new approach to genetic-based association studies [J].

Devlin, B ;

Roeder, K ;

Wasserman, L .

THEORETICAL POPULATION BIOLOGY, 2001, 60 (03) :155-166

[7] Evolving concepts of rheumatoid arthritis [J].

Firestein, GS .

NATURE, 2003, 423 (6937) :356-361

[8] 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

[9] REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis [J].

Gregersen, Peter K. ;

Amos, Chistopher I. ;

Lee, Annette T. ;

Lu, Yue ;

Remmers, Elaine F. ;

Kastner, Daniel L. ;

Seldin, Michael F. ;

Criswell, Lindsey A. ;

Plenge, Robert M. ;

Holers, V. Michael ;

Mikuls, Ted R. ;

Sokka, Tuulikki ;

Moreland, Larry W. ;

Bridges, S. Louis, Jr. ;

Xie, Gang ;

Begovich, Ann B. ;

Siminovitch, Katherine A. .

NATURE GENETICS, 2009, 41 (07) :820-U77

[10] CCR6 and NK1.1 distinguish between IL-17A and IFN-γ-producing γδ effector T cells [J].

Haas, Jan D. ;

Malinarich Gonzalez, Frano H. ;

Schmitz, Susanne ;

Chennupati, Vijaykumar ;

Foehse, Lisa ;

Kremmer, Elisabeth ;

Foerster, Reinhold ;

Prinz, Immo .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2009, 39 (12) :3488-3497

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