Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

David Ellinghaus, Hu Zhang, Sebastian Zeissig, Simone Lipinski, Andreas Till, Tao Jiang, Björn Stade, Yana Bromberg, Eva Ellinghaus, Andreas Keller, Manuel A Rivas, Jurgita Skieceviciene, Nadezhda T Doncheva, Xiao Liu, Qing Liu, Fuman Jiang, Michael Forster, Gabriele Mayr, Mario Albrecht, Robert HäslerBernhard O Boehm, Jane Goodall, Carlo R Berzuini, James Lee, Vibeke Andersen, Ulla Birgitte Vogel, Limas Kupcinskas, Manfred Kayser, Michael Krawczak, Susanna Nikolaus, Rinse K Weersma, Cyriel Y Ponsioen, Miquel Sans, Cisca Wijmenga, David P Strachan, Wendy L McArdle, Séverine Vermeire, Paul Rutgeerts, Jeremy D Sanderson, Christopher G Mathew, Morten H Vatn, Jun Wang, Markus M Nöthen, Richard H Duerr, Carsten Büning, Stephan Brand, Jürgen Glas, Juliane Winkelmann, Thomas Illig, Anna Latiano, Vito Annese, Jonas Halfvarson, Mauro D'Amato, Mark J Daly, Michael Nothnagel, Tom H Karlsen, Suresh Subramani, Philip Rosenstiel, Stefan Schreiber, Miles Parkes, Andre Franke

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Resumé

BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
OriginalsprogEngelsk
Artikelnummer23727859
TidsskriftGastroenterology
Vol/bind145
Udgave nummer2
Sider (fra-til)339-347
Antal sider9
ISSN0016-5085
DOI
StatusUdgivet - 25. apr. 2013

Fingeraftryk

Exome
Crohn Disease
Genome-Wide Association Study
Proteins
L-Selectin
Mutation
Missense Mutation
Ulcerative Colitis
Computer Simulation
Meta-Analysis
Alleles

Citer dette

Ellinghaus, David ; Zhang, Hu ; Zeissig, Sebastian ; Lipinski, Simone ; Till, Andreas ; Jiang, Tao ; Stade, Björn ; Bromberg, Yana ; Ellinghaus, Eva ; Keller, Andreas ; Rivas, Manuel A ; Skieceviciene, Jurgita ; Doncheva, Nadezhda T ; Liu, Xiao ; Liu, Qing ; Jiang, Fuman ; Forster, Michael ; Mayr, Gabriele ; Albrecht, Mario ; Häsler, Robert ; Boehm, Bernhard O ; Goodall, Jane ; Berzuini, Carlo R ; Lee, James ; Andersen, Vibeke ; Vogel, Ulla Birgitte ; Kupcinskas, Limas ; Kayser, Manfred ; Krawczak, Michael ; Nikolaus, Susanna ; Weersma, Rinse K ; Ponsioen, Cyriel Y ; Sans, Miquel ; Wijmenga, Cisca ; Strachan, David P ; McArdle, Wendy L ; Vermeire, Séverine ; Rutgeerts, Paul ; Sanderson, Jeremy D ; Mathew, Christopher G ; Vatn, Morten H ; Wang, Jun ; Nöthen, Markus M ; Duerr, Richard H ; Büning, Carsten ; Brand, Stephan ; Glas, Jürgen ; Winkelmann, Juliane ; Illig, Thomas ; Latiano, Anna ; Annese, Vito ; Halfvarson, Jonas ; D'Amato, Mauro ; Daly, Mark J ; Nothnagel, Michael ; Karlsen, Tom H ; Subramani, Suresh ; Rosenstiel, Philip ; Schreiber, Stefan ; Parkes, Miles ; Franke, Andre. / Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies. I: Gastroenterology. 2013 ; Bind 145, Nr. 2. s. 339-347.
@article{245d961297c647dbad816b0b69f2ccfe,
title = "Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies",
abstract = "BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.",
author = "David Ellinghaus and Hu Zhang and Sebastian Zeissig and Simone Lipinski and Andreas Till and Tao Jiang and Bj{\"o}rn Stade and Yana Bromberg and Eva Ellinghaus and Andreas Keller and Rivas, {Manuel A} and Jurgita Skieceviciene and Doncheva, {Nadezhda T} and Xiao Liu and Qing Liu and Fuman Jiang and Michael Forster and Gabriele Mayr and Mario Albrecht and Robert H{\"a}sler and Boehm, {Bernhard O} and Jane Goodall and Berzuini, {Carlo R} and James Lee and Vibeke Andersen and Vogel, {Ulla Birgitte} and Limas Kupcinskas and Manfred Kayser and Michael Krawczak and Susanna Nikolaus and Weersma, {Rinse K} and Ponsioen, {Cyriel Y} and Miquel Sans and Cisca Wijmenga and Strachan, {David P} and McArdle, {Wendy L} and S{\'e}verine Vermeire and Paul Rutgeerts and Sanderson, {Jeremy D} and Mathew, {Christopher G} and Vatn, {Morten H} and Jun Wang and N{\"o}then, {Markus M} and Duerr, {Richard H} and Carsten B{\"u}ning and Stephan Brand and J{\"u}rgen Glas and Juliane Winkelmann and Thomas Illig and Anna Latiano and Vito Annese and Jonas Halfvarson and Mauro D'Amato and Daly, {Mark J} and Michael Nothnagel and Karlsen, {Tom H} and Suresh Subramani and Philip Rosenstiel and Stefan Schreiber and Miles Parkes and Andre Franke",
note = "Copyright {\circledC} 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2013",
month = "4",
day = "25",
doi = "10.1053/j.gastro.2013.04.040",
language = "English",
volume = "145",
pages = "339--347",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Heinemann",
number = "2",

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Ellinghaus, D, Zhang, H, Zeissig, S, Lipinski, S, Till, A, Jiang, T, Stade, B, Bromberg, Y, Ellinghaus, E, Keller, A, Rivas, MA, Skieceviciene, J, Doncheva, NT, Liu, X, Liu, Q, Jiang, F, Forster, M, Mayr, G, Albrecht, M, Häsler, R, Boehm, BO, Goodall, J, Berzuini, CR, Lee, J, Andersen, V, Vogel, UB, Kupcinskas, L, Kayser, M, Krawczak, M, Nikolaus, S, Weersma, RK, Ponsioen, CY, Sans, M, Wijmenga, C, Strachan, DP, McArdle, WL, Vermeire, S, Rutgeerts, P, Sanderson, JD, Mathew, CG, Vatn, MH, Wang, J, Nöthen, MM, Duerr, RH, Büning, C, Brand, S, Glas, J, Winkelmann, J, Illig, T, Latiano, A, Annese, V, Halfvarson, J, D'Amato, M, Daly, MJ, Nothnagel, M, Karlsen, TH, Subramani, S, Rosenstiel, P, Schreiber, S, Parkes, M & Franke, A 2013, 'Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies', Gastroenterology, bind 145, nr. 2, 23727859, s. 339-347. https://doi.org/10.1053/j.gastro.2013.04.040

Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies. / Ellinghaus, David; Zhang, Hu; Zeissig, Sebastian; Lipinski, Simone; Till, Andreas; Jiang, Tao; Stade, Björn; Bromberg, Yana; Ellinghaus, Eva; Keller, Andreas; Rivas, Manuel A; Skieceviciene, Jurgita; Doncheva, Nadezhda T; Liu, Xiao; Liu, Qing; Jiang, Fuman; Forster, Michael; Mayr, Gabriele; Albrecht, Mario; Häsler, Robert; Boehm, Bernhard O; Goodall, Jane; Berzuini, Carlo R; Lee, James; Andersen, Vibeke; Vogel, Ulla Birgitte; Kupcinskas, Limas; Kayser, Manfred; Krawczak, Michael; Nikolaus, Susanna; Weersma, Rinse K; Ponsioen, Cyriel Y; Sans, Miquel; Wijmenga, Cisca; Strachan, David P; McArdle, Wendy L; Vermeire, Séverine; Rutgeerts, Paul; Sanderson, Jeremy D; Mathew, Christopher G; Vatn, Morten H; Wang, Jun; Nöthen, Markus M; Duerr, Richard H; Büning, Carsten; Brand, Stephan; Glas, Jürgen; Winkelmann, Juliane; Illig, Thomas; Latiano, Anna; Annese, Vito; Halfvarson, Jonas; D'Amato, Mauro; Daly, Mark J; Nothnagel, Michael; Karlsen, Tom H; Subramani, Suresh; Rosenstiel, Philip; Schreiber, Stefan; Parkes, Miles; Franke, Andre.

I: Gastroenterology, Bind 145, Nr. 2, 23727859, 25.04.2013, s. 339-347.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

AU - Ellinghaus, David

AU - Zhang, Hu

AU - Zeissig, Sebastian

AU - Lipinski, Simone

AU - Till, Andreas

AU - Jiang, Tao

AU - Stade, Björn

AU - Bromberg, Yana

AU - Ellinghaus, Eva

AU - Keller, Andreas

AU - Rivas, Manuel A

AU - Skieceviciene, Jurgita

AU - Doncheva, Nadezhda T

AU - Liu, Xiao

AU - Liu, Qing

AU - Jiang, Fuman

AU - Forster, Michael

AU - Mayr, Gabriele

AU - Albrecht, Mario

AU - Häsler, Robert

AU - Boehm, Bernhard O

AU - Goodall, Jane

AU - Berzuini, Carlo R

AU - Lee, James

AU - Andersen, Vibeke

AU - Vogel, Ulla Birgitte

AU - Kupcinskas, Limas

AU - Kayser, Manfred

AU - Krawczak, Michael

AU - Nikolaus, Susanna

AU - Weersma, Rinse K

AU - Ponsioen, Cyriel Y

AU - Sans, Miquel

AU - Wijmenga, Cisca

AU - Strachan, David P

AU - McArdle, Wendy L

AU - Vermeire, Séverine

AU - Rutgeerts, Paul

AU - Sanderson, Jeremy D

AU - Mathew, Christopher G

AU - Vatn, Morten H

AU - Wang, Jun

AU - Nöthen, Markus M

AU - Duerr, Richard H

AU - Büning, Carsten

AU - Brand, Stephan

AU - Glas, Jürgen

AU - Winkelmann, Juliane

AU - Illig, Thomas

AU - Latiano, Anna

AU - Annese, Vito

AU - Halfvarson, Jonas

AU - D'Amato, Mauro

AU - Daly, Mark J

AU - Nothnagel, Michael

AU - Karlsen, Tom H

AU - Subramani, Suresh

AU - Rosenstiel, Philip

AU - Schreiber, Stefan

AU - Parkes, Miles

AU - Franke, Andre

N1 - Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2013/4/25

Y1 - 2013/4/25

N2 - BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

AB - BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

U2 - 10.1053/j.gastro.2013.04.040

DO - 10.1053/j.gastro.2013.04.040

M3 - Journal article

C2 - 23624108

VL - 145

SP - 339

EP - 347

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

M1 - 23727859

ER -