Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Andre Franke; Tobias Balschun; Tom H. Karlsen; Jurgita Sventoraityte; Susanna Nikolaus; Gabriele Mayr; Francisco S. Domingues; Mario Albrecht; Michael Nothnagel; David Ellinghaus; Christian Sina; Clive M. Onnie; Rinse K. Weersma; Pieter C.F. Stokkers; Cisca Wijmenga; Maria Gazouli; David Strachan; Wendy L. McArdle; Séverine Vermeire; Paul Rutgeerts; Philip Rosenstiel; Michael Krawczak; Morten H. Vatn; Christopher G. Mathew; Stefan Schreiber

doi:10.1038/ng.221

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Andre Franke, Tobias Balschun, Tom H. Karlsen, Jurgita Sventoraityte, Susanna Nikolaus, Gabriele Mayr, Francisco S. Domingues, Mario Albrecht, Michael Nothnagel, David Ellinghaus, Christian Sina, Clive M. Onnie, Rinse K. Weersma, Pieter C.F. Stokkers, Cisca Wijmenga, Maria Gazouli, David Strachan, Wendy L. McArdle, Séverine Vermeire, Paul RutgeertsPhilip Rosenstiel, Michael Krawczak, Morten H. Vatn, Christopher G. Mathew, Stefan Schreiber^*

^*Corresponding author for this work

453 Citations (Scopus)

Abstract

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 ^-12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

Original language	English
Journal	Nature Genetics
Volume	40
Issue number	11
Pages (from-to)	1319-1323
Number of pages	5
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.221
Publication status	Published - 11.2008

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

UN SDGs

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

Access to Document

10.1038/ng.221

Cite this

Franke, A., Balschun, T., Karlsen, T. H., Sventoraityte, J., Nikolaus, S., Mayr, G., Domingues, F. S., Albrecht, M., Nothnagel, M., Ellinghaus, D., Sina, C., Onnie, C. M., Weersma, R. K., Stokkers, P. C. F., Wijmenga, C., Gazouli, M., Strachan, D., McArdle, W. L., Vermeire, S., ... Schreiber, S. (2008). Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature Genetics, 40(11), 1319-1323. https://doi.org/10.1038/ng.221

@article{2d5ce78844a0409f98f3c0471772fa6a,

title = "Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility",

abstract = "Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.",

author = "Andre Franke and Tobias Balschun and Karlsen, {Tom H.} and Jurgita Sventoraityte and Susanna Nikolaus and Gabriele Mayr and Domingues, {Francisco S.} and Mario Albrecht and Michael Nothnagel and David Ellinghaus and Christian Sina and Onnie, {Clive M.} and Weersma, {Rinse K.} and Stokkers, {Pieter C.F.} and Cisca Wijmenga and Maria Gazouli and David Strachan and McArdle, {Wendy L.} and S{\'e}verine Vermeire and Paul Rutgeerts and Philip Rosenstiel and Michael Krawczak and Vatn, {Morten H.} and Mathew, {Christopher G.} and Stefan Schreiber",

note = "Funding Information: We wish to thank all individuals with IBD, families and physicians for their cooperation. We gratefully acknowledge the cooperation of the German Crohn and Colitis Foundation (Deutsche Morbus Crohn und Colitis Vereinigung e.V.), the BMBF competence network {\textquoteleft}{\textquoteleft}IBD{\textquoteright}{\textquoteright} and of the contributing gastroenterologists. Finally, we wish to thank T. Wesse, T. Henke, A. Dietsch, R. Vogler, C.v.d. Lancken and M. Friskovec for expert technical help. We thank T. Wienker and M. Steffens (IMBIE, University of Bonn) for performing the quality control of the GWAS datasets. We thank B.A. Lie and the Norwegian Bone Marrow Donor Registry at Rikshospitalet University Hospital, Oslo, for contributing the healthy Norwegian control population. This study was supported by the German Ministry of Education and Research (BMBF) through the Copyright: Copyright 2009 Elsevier B.V., All rights reserved.",

year = "2008",

month = nov,

doi = "10.1038/ng.221",

language = "English",

volume = "40",

pages = "1319--1323",

journal = "Nature Genetics",

issn = "1061-4036",

number = "11",

}

Franke, A, Balschun, T, Karlsen, TH, Sventoraityte, J, Nikolaus, S, Mayr, G, Domingues, FS, Albrecht, M, Nothnagel, M, Ellinghaus, D, Sina, C, Onnie, CM, Weersma, RK, Stokkers, PCF, Wijmenga, C, Gazouli, M, Strachan, D, McArdle, WL, Vermeire, S, Rutgeerts, P, Rosenstiel, P, Krawczak, M, Vatn, MH, Mathew, CG & Schreiber, S 2008, 'Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility', Nature Genetics, vol. 40, no. 11, pp. 1319-1323. https://doi.org/10.1038/ng.221

TY - JOUR

T1 - Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

AU - Franke, Andre

AU - Balschun, Tobias

AU - Karlsen, Tom H.

AU - Sventoraityte, Jurgita

AU - Nikolaus, Susanna

AU - Mayr, Gabriele

AU - Domingues, Francisco S.

AU - Albrecht, Mario

AU - Nothnagel, Michael

AU - Ellinghaus, David

AU - Sina, Christian

AU - Onnie, Clive M.

AU - Weersma, Rinse K.

AU - Stokkers, Pieter C.F.

AU - Wijmenga, Cisca

AU - Gazouli, Maria

AU - Strachan, David

AU - McArdle, Wendy L.

AU - Vermeire, Séverine

AU - Rutgeerts, Paul

AU - Rosenstiel, Philip

AU - Krawczak, Michael

AU - Vatn, Morten H.

AU - Mathew, Christopher G.

AU - Schreiber, Stefan

N1 - Funding Information: We wish to thank all individuals with IBD, families and physicians for their cooperation. We gratefully acknowledge the cooperation of the German Crohn and Colitis Foundation (Deutsche Morbus Crohn und Colitis Vereinigung e.V.), the BMBF competence network ‘‘IBD’’ and of the contributing gastroenterologists. Finally, we wish to thank T. Wesse, T. Henke, A. Dietsch, R. Vogler, C.v.d. Lancken and M. Friskovec for expert technical help. We thank T. Wienker and M. Steffens (IMBIE, University of Bonn) for performing the quality control of the GWAS datasets. We thank B.A. Lie and the Norwegian Bone Marrow Donor Registry at Rikshospitalet University Hospital, Oslo, for contributing the healthy Norwegian control population. This study was supported by the German Ministry of Education and Research (BMBF) through the Copyright: Copyright 2009 Elsevier B.V., All rights reserved.

PY - 2008/11

Y1 - 2008/11

N2 - Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

AB - Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

UR - http://www.scopus.com/inward/record.url?scp=55049111426&partnerID=8YFLogxK

U2 - 10.1038/ng.221

DO - 10.1038/ng.221

M3 - Journal articles

C2 - 18836448

AN - SCOPUS:55049111426

SN - 1061-4036

VL - 40

SP - 1319

EP - 1323

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Abstract

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this