A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
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A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. / Heinig, Matthias; Petretto, Enrico; Wallace, Chris; Bottolo, Leonardo; Rotival, Maxime; Lu, Han; Li, Yoyo; Sarwar, Rizwan; Langley, Sarah R; Bauerfeind, Anja; Hummel, Oliver; Lee, Young-Ae; Paskas, Svetlana; Rintisch, Carola; Saar, Kathrin; Cooper, Jason; Buchan, Rachel; Gray, Elizabeth E; Cyster, Jason G; Erdmann, Jeanette; Hengstenberg, Christian; Maouche, Seraya; Ouwehand, Willem H; Rice, Catherine M; Samani, Nilesh J; Schunkert, Heribert; Goodall, Alison H; Schulz, Herbert; Roider, Helge G; Vingron, Martin; Blankenberg, Stefan; Münzel, Thomas; Zeller, Tanja; Szymczak, Silke; Ziegler, Andreas; Tiret, Laurence; Smyth, Deborah J; Pravenec, Michal; Aitman, Timothy J; Cambien, Francois; Clayton, David; Todd, John A; Hubner, Norbert; Cook, Stuart A; CardioGenics Consortium.
in: NATURE, Jahrgang 467, Nr. 7314, 23.09.2010, S. 460-464.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
AU - Heinig, Matthias
AU - Petretto, Enrico
AU - Wallace, Chris
AU - Bottolo, Leonardo
AU - Rotival, Maxime
AU - Lu, Han
AU - Li, Yoyo
AU - Sarwar, Rizwan
AU - Langley, Sarah R
AU - Bauerfeind, Anja
AU - Hummel, Oliver
AU - Lee, Young-Ae
AU - Paskas, Svetlana
AU - Rintisch, Carola
AU - Saar, Kathrin
AU - Cooper, Jason
AU - Buchan, Rachel
AU - Gray, Elizabeth E
AU - Cyster, Jason G
AU - Erdmann, Jeanette
AU - Hengstenberg, Christian
AU - Maouche, Seraya
AU - Ouwehand, Willem H
AU - Rice, Catherine M
AU - Samani, Nilesh J
AU - Schunkert, Heribert
AU - Goodall, Alison H
AU - Schulz, Herbert
AU - Roider, Helge G
AU - Vingron, Martin
AU - Blankenberg, Stefan
AU - Münzel, Thomas
AU - Zeller, Tanja
AU - Szymczak, Silke
AU - Ziegler, Andreas
AU - Tiret, Laurence
AU - Smyth, Deborah J
AU - Pravenec, Michal
AU - Aitman, Timothy J
AU - Cambien, Francois
AU - Clayton, David
AU - Todd, John A
AU - Hubner, Norbert
AU - Cook, Stuart A
AU - CardioGenics Consortium
PY - 2010/9/23
Y1 - 2010/9/23
N2 - 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. 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)-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, 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)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 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.
AB - 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. 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)-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, 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)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 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.
KW - Animals
KW - Base Sequence
KW - Chromosomes, Human, Pair 13/genetics
KW - Chromosomes, Mammalian/genetics
KW - Diabetes Mellitus, Type 1/genetics
KW - Gene Regulatory Networks/genetics
KW - Genetic Loci/genetics
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Immunity, Innate/genetics
KW - Inflammation/genetics
KW - Interferon Regulatory Factor-7/immunology
KW - Macrophages/immunology
KW - Organ Specificity
KW - Polymorphism, Single Nucleotide/genetics
KW - Quantitative Trait Loci/genetics
KW - Rats
KW - Receptors, G-Protein-Coupled/genetics
KW - Viruses/immunology
U2 - 10.1038/nature09386
DO - 10.1038/nature09386
M3 - SCORING: Journal article
C2 - 20827270
VL - 467
SP - 460
EP - 464
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7314
ER -