A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

被引：224

作者：

Heinig, Matthias ^{[1
,2
]}

Petretto, Enrico ^{[3
,4
]}

Wallace, Chris ^{[5
]}

Bottolo, Leonardo ^{[3
,4
]}

Rotival, Maxime ^{[6
,7
]}

Lu, Han ^{[3
]}

Li, Yoyo ^{[3
]}

Sarwar, Rizwan ^{[3
]}

Langley, Sarah R. ^{[3
]}

Bauerfeind, Anja ^{[1
]}

Hummel, Oliver ^{[1
]}

Lee, Young-Ae ^{[1
,8
]}

Paskas, Svetlana ^{[1
]}

Rintisch, Carola ^{[1
]}

Saar, Kathrin ^{[1
]}

Cooper, Jason ^{[5
]}

Buchan, Rachel ^{[3
]}

Gray, Elizabeth E. ^{[9
,10
]}

Cyster, Jason G. ^{[9
,10
]}

Erdmann, Jeanette ^{[11
]}

Hengstenberg, Christian ^{[12
]}

Maouche, Seraya ^{[6
,7
]}

Ouwehand, Willem H. ^{[13
,14
,15
]}

Rice, Catherine M. ^{[15
]}

Samani, Nilesh J. ^{[16
,17
]}

Schunkert, Heribert ^{[11
]}

Goodall, Alison H. ^{[16
,17
]}

Schulz, Herbert ^{[1
]}

Roider, Helge G. ^{[2
]}

Vingron, Martin ^{[2
]}

Blankenberg, Stefan ^{[18
]}

Muenzel, Thomas ^{[18
]}

Zeller, Tanja ^{[18
]}

Szymczak, Silke ^{[19
]}

Ziegler, Andreas ^{[19
]}

Tiret, Laurence ^{[6
,7
]}

Smyth, Deborah J. ^{[5
]}

Pravenec, Michal ^{[20
,21
]}

Aitman, Timothy J. ^{[3
]}

Cambien, Francois ^{[6
,7
]}

Clayton, David ^{[5
]}

Todd, John A. ^{[5
]}

Hubner, Norbert ^{[1
,22
]}

Cook, Stuart A. ^{[3
,23
]}

机构：

[1] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[2] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[3] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Fac Med, Med Res Council,Clin Sci Ctr, London W12 0NN, England

[4] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Epidemiol & Biostat, London W2 1PG, England

[5] Univ Cambridge, Cambridge Inst Med Res, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab, Cambridge CB2 0XY, England

[6] Univ Paris 06, INSERM, UMRS 937, F-75013 Paris, France

[7] Sch Med, F-75013 Paris, France

[8] Charite, D-13353 Berlin, Germany

[9] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[10] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[11] Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[12] Univ Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany

[13] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England

[14] Natl Hlth Serv Blood & Transplant, Cambridge CB2 0PT, England

[15] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[16] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England

[17] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England

[18] Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, D-55131 Mainz, Germany

[19] Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, D-23562 Lubeck, Germany

[20] Acad Sci Czech Republic, Inst Physiol, Prague 14220 4, Czech Republic

[21] Ctr Appl Genom, Prague 14220 4, Czech Republic

[22] Charite, CC4, D-10117 Berlin, Germany

[23] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England

来源：

NATURE | 2010年 / 467卷 / 7314期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; TRANSCRIPTION FACTORS; MOLECULAR NETWORKS; GENE-EXPRESSION; DISEASE; INFLAMMATION; RESPONSES; IFIH1; SNPS; RAT;

D O I：

10.1038/nature09386

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches(1,2). Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7(3))-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration(4,5), is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-amacrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 x 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 x 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

引用

页码：460 / 464

页数：5

共 29 条

[1] Genetic Mapping in Human Disease [J].

Altshuler, David ;

Daly, Mark J. ;

Lander, Eric S. .

SCIENCE, 2008, 322 (5903) :881-888

[2] The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance [J].

Atanur, Santosh S. ;

Birol, Inanc ;

Guryev, Victor ;

Hirst, Martin ;

Hummel, Oliver ;

Morrissey, Catherine ;

Behmoaras, Jacques ;

Fernandez-Suarez, Xose M. ;

Johnson, Michelle D. ;

McLaren, William M. ;

Patone, Giannino ;

Petretto, Enrico ;

Plessy, Charles ;

Rockland, Kathleen S. ;

Rockland, Charles ;

Saar, Kathrin ;

Zhao, Yongjun ;

Carninci, Piero ;

Flicek, Paul ;

Kurtz, Ted ;

Cuppen, Edwin ;

Pravenec, Michal ;

Hubner, Norbert ;

Jones, Steven J. M. ;

Birney, Ewan ;

Aitman, Timothy J. .

GENOME RESEARCH, 2010, 20 (06) :791-803

[3] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[4] Genetical Genomics: Spotlight on QTL Hotspots [J].

Breitling, Rainer ;

Li, Yang ;

Tesson, Bruno M. ;

Fu, Jingyuan ;

Wu, Chunlei ;

Wiltshire, Tim ;

Gerrits, Alice ;

Bystrykh, Leonid V. ;

de Haan, Gerald ;

Su, Andrew I. ;

Jansen, Ritsert C. .

PLOS GENETICS, 2008, 4 (10)

[5] Genetic dissection of transcriptional regulation in budding yeast [J].

Brem, RB ;

Yvert, G ;

Clinton, R ;

Kruglyak, L .

SCIENCE, 2002, 296 (5568) :752-755

[6] 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

[7] Variations in DNA elucidate molecular networks that cause disease [J].

Chen, Yanqing ;

Zhu, Jun ;

Lum, Pek Yee ;

Yang, Xia ;

Pinto, Shirly ;

MacNeil, Douglas J. ;

Zhang, Chunsheng ;

Lamb, John ;

Edwards, Stephen ;

Sieberts, Solveig K. ;

Leonardson, Amy ;

Castellini, Lawrence W. ;

Wang, Susanna ;

Champy, Marie-France ;

Zhang, Bin ;

Emilsson, Valur ;

Doss, Sudheer ;

Ghazalpour, Anatole ;

Horvath, Steve ;

Drake, Thomas A. ;

Lusis, Aldons J. ;

Schadt, Eric E. .

NATURE, 2008, 452 (7186) :429-435

[8] Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families [J].

Cooper, J. D. ;

Walker, N. M. ;

Smyth, D. J. ;

Downes, K. ;

Healy, B. C. ;

Todd, J. A. .

GENES AND IMMUNITY, 2009, 10 :S85-S94

[9] Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner [J].

Dimas, Antigone S. ;

Deutsch, Samuel ;

Stranger, Barbara E. ;

Montgomery, Stephen B. ;

Borel, Christelle ;

Attar-Cohen, Homa ;

Ingle, Catherine ;

Beazley, Claude ;

Arcelus, Maria Gutierrez ;

Sekowska, Magdalena ;

Gagnebin, Marilyne ;

Nisbett, James ;

Deloukas, Panos ;

Dermitzakis, Emmanouil T. ;

Antonarakis, Stylianos E. .

SCIENCE, 2009, 325 (5945) :1246-1250

[10] The role of inflammation in insulitis and β-cell loss in type 1 diabetes [J].

Eizirik, Decio L. ;

Colli, Maikel L. ;

Ortis, Fernanda .

NATURE REVIEWS ENDOCRINOLOGY, 2009, 5 (04) :219-226

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