Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Cardiogenics Consortium

doi:10.1093/hmg/ddr468

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Cardiogenics Consortium

Department of Education

University of Cambridge

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

94 Citations (SciVal)

Abstract

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

Original language	English
Pages (from-to)	322-333
Number of pages	12
Journal	Human Molecular Genetics
Volume	21
Issue number	2
Early online date	11 Oct 2011
DOIs	https://doi.org/10.1093/hmg/ddr468
Publication status	Published - 15 Jan 2012

Bibliographical note

© The Author 2011. Published by Oxford University Press.
Funding Information:
We acknowledge the use of DNA from The UK Blood Services collection of Common Controls (UKBS collection), funded by the Wellcome Trust grant 076113/C/04/Z, by the Wellcome Trust/Juvenile Diabetes Research Foundation grant 061858 and by the National Institute of Health Research of England. The collection was established as part of the Wellcome Trust Case-Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. L.J.D. is supported by a Wellcome Trust Intermediate Clinical Fellowship (082549/Z/07/Z). C.W. is supported by a Wellcome Trust Career Development Fellowship (089989/Z/09/Z). K.L.A. is supported by a 4-year Wellcome Trust CIMR PhD studentship. N.K.W. is supported by the Medical Research Council. N.S. and A.A. are supported by King Saud bin Abdulaziz University of Health Sciences and the Saudi Ministry for Higher Education. This work was funded by the Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (079895). The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (Stiftung Rheinland Pfalz für Innovation, contract number AZ 961-386261/733), the research programs Wissen schafft Zukunft and Schwerpunkt Vaskuläre Prävention of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Health Study. Specifically, the research reported in this article was supported by the National Genome Network NGFNplus (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

Keywords

Autoimmune Diseases/genetics
Chromosomes, Human, Pair 16
DNA/genetics
DNA-Binding Proteins/genetics
Humans
Membrane Proteins/genetics
Monocytes/metabolism
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Quantitative Trait Loci

UN SDGs

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

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10.1093/hmg/ddr468Licence: CC BY-NC

Cite this

@article{30eb6e723fc34267aedea243184de1ed,

title = "Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene",

abstract = "The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.",

keywords = "Autoimmune Diseases/genetics, Chromosomes, Human, Pair 16, DNA/genetics, DNA-Binding Proteins/genetics, Humans, Membrane Proteins/genetics, Monocytes/metabolism, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Quantitative Trait Loci",

author = "{Cardiogenics Consortium} and Davison, {Lucy J} and Chris Wallace and Jason Cooper and Cope, {Nathan F} and Wilson, {Nicola K} and Smyth, {Deborah J} and Howson, {Joanna M M} and Nada Saleh and Abdullah Al-Jeffery and Angus, {Karen L} and Stevens, {Helen E} and Sarah Nutland and Simon Duley and Coulson, {Richard M R} and Walker, {Neil M} and Burren, {Oliver S} and Rice, {Catherine M} and Francois Cambien and Tanja Zeller and Thomas Munzel and Karl Lackner and Stefan Blakenberg and Peter Fraser and Berthold Gottgens and Todd, {John A} and Tony Attwood and Stephanie Belz and Peter Braund and Fran{\c c}ois Cambien and Jason Cooper and Abi Crisp-Hihn and Patrick Diemert and Panos Deloukas and Nicola Foad and Jeanette Erdmann and Goodall, {Alison H} and Jay Gracey and Emma Gray and Williams, {Rhian G} and Susanne Heimerl and Christian Hengstenberg and Jennifer Jolley and Unni Krishnan and Heather Lloyd-Jones and Ingrid Lugauer and Per Lundmark and Seraya Maouche and Moore, {Jasbir S} and David Muir and Elizabeth Murray",

note = "{\textcopyright} The Author 2011. Published by Oxford University Press. Funding Information: We acknowledge the use of DNA from The UK Blood Services collection of Common Controls (UKBS collection), funded by the Wellcome Trust grant 076113/C/04/Z, by the Wellcome Trust/Juvenile Diabetes Research Foundation grant 061858 and by the National Institute of Health Research of England. The collection was established as part of the Wellcome Trust Case-Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. L.J.D. is supported by a Wellcome Trust Intermediate Clinical Fellowship (082549/Z/07/Z). C.W. is supported by a Wellcome Trust Career Development Fellowship (089989/Z/09/Z). K.L.A. is supported by a 4-year Wellcome Trust CIMR PhD studentship. N.K.W. is supported by the Medical Research Council. N.S. and A.A. are supported by King Saud bin Abdulaziz University of Health Sciences and the Saudi Ministry for Higher Education. This work was funded by the Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (079895). The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (Stiftung Rheinland Pfalz f{\"u}r Innovation, contract number AZ 961-386261/733), the research programs Wissen schafft Zukunft and Schwerpunkt Vaskul{\"a}re Pr{\"a}vention of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Health Study. Specifically, the research reported in this article was supported by the National Genome Network NGFNplus (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.",

year = "2012",

month = jan,

day = "15",

doi = "10.1093/hmg/ddr468",

language = "English",

volume = "21",

pages = "322--333",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

AU - Cardiogenics Consortium

AU - Davison, Lucy J

AU - Wallace, Chris

AU - Cooper, Jason

AU - Cope, Nathan F

AU - Wilson, Nicola K

AU - Smyth, Deborah J

AU - Howson, Joanna M M

AU - Saleh, Nada

AU - Al-Jeffery, Abdullah

AU - Angus, Karen L

AU - Stevens, Helen E

AU - Nutland, Sarah

AU - Duley, Simon

AU - Coulson, Richard M R

AU - Walker, Neil M

AU - Burren, Oliver S

AU - Rice, Catherine M

AU - Cambien, Francois

AU - Zeller, Tanja

AU - Munzel, Thomas

AU - Lackner, Karl

AU - Blakenberg, Stefan

AU - Fraser, Peter

AU - Gottgens, Berthold

AU - Todd, John A

AU - Attwood, Tony

AU - Belz, Stephanie

AU - Braund, Peter

AU - Cambien, François

AU - Cooper, Jason

AU - Crisp-Hihn, Abi

AU - Diemert, Patrick

AU - Deloukas, Panos

AU - Foad, Nicola

AU - Erdmann, Jeanette

AU - Goodall, Alison H

AU - Gracey, Jay

AU - Gray, Emma

AU - Williams, Rhian G

AU - Heimerl, Susanne

AU - Hengstenberg, Christian

AU - Jolley, Jennifer

AU - Krishnan, Unni

AU - Lloyd-Jones, Heather

AU - Lugauer, Ingrid

AU - Lundmark, Per

AU - Maouche, Seraya

AU - Moore, Jasbir S

AU - Muir, David

AU - Murray, Elizabeth

N1 - © The Author 2011. Published by Oxford University Press. Funding Information: We acknowledge the use of DNA from The UK Blood Services collection of Common Controls (UKBS collection), funded by the Wellcome Trust grant 076113/C/04/Z, by the Wellcome Trust/Juvenile Diabetes Research Foundation grant 061858 and by the National Institute of Health Research of England. The collection was established as part of the Wellcome Trust Case-Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. L.J.D. is supported by a Wellcome Trust Intermediate Clinical Fellowship (082549/Z/07/Z). C.W. is supported by a Wellcome Trust Career Development Fellowship (089989/Z/09/Z). K.L.A. is supported by a 4-year Wellcome Trust CIMR PhD studentship. N.K.W. is supported by the Medical Research Council. N.S. and A.A. are supported by King Saud bin Abdulaziz University of Health Sciences and the Saudi Ministry for Higher Education. This work was funded by the Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (079895). The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (Stiftung Rheinland Pfalz für Innovation, contract number AZ 961-386261/733), the research programs Wissen schafft Zukunft and Schwerpunkt Vaskuläre Prävention of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems including an unrestricted grant for the Gutenberg Health Study. Specifically, the research reported in this article was supported by the National Genome Network NGFNplus (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

PY - 2012/1/15

Y1 - 2012/1/15

N2 - The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

AB - The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

KW - Autoimmune Diseases/genetics

KW - Chromosomes, Human, Pair 16

KW - DNA/genetics

KW - DNA-Binding Proteins/genetics

KW - Humans

KW - Membrane Proteins/genetics

KW - Monocytes/metabolism

KW - Polymerase Chain Reaction

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

U2 - 10.1093/hmg/ddr468

DO - 10.1093/hmg/ddr468

M3 - Article

C2 - 21989056

SN - 0964-6906

VL - 21

SP - 322

EP - 333

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

ER -

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Abstract

Bibliographical note

Keywords

UN SDGs

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