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

Matthias Heinig; Enrico Petretto; Chris Wallace; Leonardo Bottolo; Maxime Rotival; Han Lu; Yoyo Li; Rizwan Sarwar; Sarah R Langley; Anja Bauerfeind; Oliver Hummel; Young-Ae Lee; Svetlana Paskas; Carola Rintisch; Kathrin Saar; Jason Cooper; Rachel Buchan; Elizabeth E Gray; Jason G Cyster; Jeanette Erdmann; Christian Hengstenberg; Seraya Maouche; Willem H Ouwehand; Catherine M Rice; Nilesh J Samani; Heribert Schunkert; Alison H Goodall; Herbert Schulz; Helge G Roider; Martin Vingron; Stefan Blankenberg; Thomas Münzel; Tanja Zeller; Silke Szymczak; Andreas Ziegler; Laurence Tiret; Deborah J Smyth; Michal Pravenec; Timothy J Aitman; Francois Cambien; David Clayton; John A Todd; Norbert Hubner; Stuart A Cook; Cardiogenics Consortium

doi:10.1038/nature09386

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

Matthias Heinig, Enrico Petretto, Chris Wallace, Leonardo Bottolo, Maxime Rotival, Han Lu, Yoyo Li, Rizwan Sarwar, Sarah R Langley, Anja Bauerfeind, Oliver Hummel, Young-Ae Lee, Svetlana Paskas, Carola Rintisch, Kathrin Saar, Jason Cooper, Rachel Buchan, Elizabeth E Gray, Jason G Cyster, Jeanette ErdmannChristian Hengstenberg, Seraya Maouche, Willem H Ouwehand, Catherine M Rice, Nilesh J Samani, Heribert Schunkert, Alison H Goodall, Herbert Schulz, Helge G Roider, Martin Vingron, Stefan Blankenberg, Thomas Münzel, Tanja Zeller, Silke Szymczak, Andreas Ziegler, Laurence Tiret, Deborah J Smyth, Michal Pravenec, Timothy J Aitman, Francois Cambien, David Clayton, John A Todd, Norbert Hubner, Stuart A Cook, Cardiogenics Consortium

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

240 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	460-4
Number of pages	5
Journal	NATURE
Volume	467
Issue number	7314
DOIs	https://doi.org/10.1038/nature09386
Publication status	Published - 23 Sept 2010

Keywords

Animals
Base Sequence
Chromosomes, Human, Pair 13
Chromosomes, Mammalian
Diabetes Mellitus, Type 1
Gene Regulatory Networks
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Immunity, Innate
Inflammation
Interferon Regulatory Factor-7
Macrophages
Organ Specificity
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Rats
Receptors, G-Protein-Coupled
Viruses

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nature09386

Cite this

Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H., Li, Y., Sarwar, R., Langley, S. R., Bauerfeind, A., Hummel, O., Lee, Y.-A., Paskas, S., Rintisch, C., Saar, K., Cooper, J., Buchan, R., Gray, E. E., Cyster, J. G., ... Cardiogenics Consortium (2010). A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. NATURE, 467(7314), 460-4. https://doi.org/10.1038/nature09386

@article{75cd5ab932ed45c6b457a9bc75f4d955,

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

abstract = "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.",

keywords = "Animals, Base Sequence, Chromosomes, Human, Pair 13, Chromosomes, Mammalian, Diabetes Mellitus, Type 1, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Immunity, Innate, Inflammation, Interferon Regulatory Factor-7, Macrophages, Organ Specificity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rats, Receptors, G-Protein-Coupled, Viruses",

author = "Matthias Heinig and Enrico Petretto and Chris Wallace and Leonardo Bottolo and Maxime Rotival and Han Lu and Yoyo Li and Rizwan Sarwar and Langley, {Sarah R} and Anja Bauerfeind and Oliver Hummel and Young-Ae Lee and Svetlana Paskas and Carola Rintisch and Kathrin Saar and Jason Cooper and Rachel Buchan and Gray, {Elizabeth E} and Cyster, {Jason G} and Jeanette Erdmann and Christian Hengstenberg and Seraya Maouche and Ouwehand, {Willem H} and Rice, {Catherine M} and Samani, {Nilesh J} and Heribert Schunkert and Goodall, {Alison H} and Herbert Schulz and Roider, {Helge G} and Martin Vingron and Stefan Blankenberg and Thomas M{\"u}nzel and Tanja Zeller and Silke Szymczak and Andreas Ziegler and Laurence Tiret and Smyth, {Deborah J} and Michal Pravenec and Aitman, {Timothy J} and Francois Cambien and David Clayton and Todd, {John A} and Norbert Hubner and Cook, {Stuart A} and {Cardiogenics Consortium}",

year = "2010",

month = sep,

day = "23",

doi = "10.1038/nature09386",

language = "English",

volume = "467",

pages = "460--4",

journal = "NATURE",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7314",

}

Heinig, M, Petretto, E, Wallace, C, Bottolo, L, Rotival, M, Lu, H, Li, Y, Sarwar, R, Langley, SR, Bauerfeind, A, Hummel, O, Lee, Y-A, Paskas, S, Rintisch, C, Saar, K, Cooper, J, Buchan, R, Gray, EE, Cyster, JG, Erdmann, J, Hengstenberg, C, Maouche, S, Ouwehand, WH, Rice, CM, Samani, NJ, Schunkert, H, Goodall, AH, Schulz, H, Roider, HG, Vingron, M, Blankenberg, S, Münzel, T, Zeller, T, Szymczak, S, Ziegler, A, Tiret, L, Smyth, DJ, Pravenec, M, Aitman, TJ, Cambien, F, Clayton, D, Todd, JA, Hubner, N, Cook, SA & Cardiogenics Consortium 2010, 'A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk', NATURE, vol. 467, no. 7314, pp. 460-4. https://doi.org/10.1038/nature09386

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

KW - Chromosomes, Mammalian

KW - Diabetes Mellitus, Type 1

KW - Gene Regulatory Networks

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Immunity, Innate

KW - Inflammation

KW - Interferon Regulatory Factor-7

KW - Macrophages

KW - Organ Specificity

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Rats

KW - Receptors, G-Protein-Coupled

KW - Viruses

U2 - 10.1038/nature09386

DO - 10.1038/nature09386

M3 - Article

C2 - 20827270

SN - 0028-0836

VL - 467

SP - 460

EP - 464

JO - NATURE

JF - NATURE

IS - 7314

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this