Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene
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Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene. / Davison, Lucy J; Wallace, Chris; Cooper, Jason D; Cope, Nathan F; Wilson, Nicola K; Smyth, Deborah J; Howson, Joanna M M; Saleh, Nada; Al-Jeffery, Abdullah; Angus, Karen L; Stevens, Helen E; Nutland, Sarah; Duley, Simon; Coulson, Richard M R; Walker, Neil M; Burren, Oliver S; Rice, Catherine M; Cambien, Francois; Zeller, Tanja; Munzel, Thomas; Lackner, Karl; Blakenberg, Stefan; Fraser, Peter; Gottgens, Berthold; Todd, John A; Attwood, Tony; Belz, Stephanie; Braund, Peter; Cambien, François; Cooper, Jason; Crisp-Hihn, Abi; Diemert, Patrick; Deloukas, Panos; Foad, Nicola; Erdmann, Jeanette; Goodall, Alison H; Gracey, Jay; Gray, Emma; Williams, Rhian G; Heimerl, Susanne; Hengstenberg, Christian; Jolley, Jennifer; Krishnan, Unni; Lloyd-Jones, Heather; Lugauer, Ingrid; Lundmark, Per; Maouche, Seraya; Moore, Jasbir S; Muir, David; Murray, Elizabeth; Nelson, Chris P; Neudert, Jessica; Niblett, David; O'Leary, Karen; Ouwehand, Willem H; Pollard, Helen; Rankin, Angela; Rice, Catherine M; Sager, Hendrik; Samani, Nilesh J; Sambrook, Jennifer; Schmitz, Gerd; Scholz, Michael; Schroeder, Laura; Schunkert, Heribert; Syvannen, Ann-Christine; Tennstedt, Stefanie; Wallace, Chris; CardioGenics Consortium.
in: HUM MOL GENET, Jahrgang 21, Nr. 2, 15.01.2012, S. 322-333.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene
AU - Davison, Lucy J
AU - Wallace, Chris
AU - Cooper, Jason D
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
AU - Nelson, Chris P
AU - Neudert, Jessica
AU - Niblett, David
AU - O'Leary, Karen
AU - Ouwehand, Willem H
AU - Pollard, Helen
AU - Rankin, Angela
AU - Rice, Catherine M
AU - Sager, Hendrik
AU - Samani, Nilesh J
AU - Sambrook, Jennifer
AU - Schmitz, Gerd
AU - Scholz, Michael
AU - Schroeder, Laura
AU - Schunkert, Heribert
AU - Syvannen, Ann-Christine
AU - Tennstedt, Stefanie
AU - Wallace, Chris
AU - CardioGenics Consortium
N1 - © The Author 2011. Published by Oxford University Press.
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 - SCORING: Journal article
C2 - 21989056
VL - 21
SP - 322
EP - 333
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 2
ER -