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

被引：132

作者：

Ellinghaus, David ^{[1
]}

Zhang, Hu ^{[3
,6
,7
]}

Zeissig, Sebastian ^{[8
]}

Lipinski, Simone ^{[1
]}

Till, Andreas ^{[10
,11
]}

Jiang, Tao ^{[12
]}

Stade, Bjoern ^{[1
]}

Bromberg, Yana ^{[13
]}

Ellinghaus, Eva ^{[1
]}

Keller, Andreas ^{[14
]}

Rivas, Manuel A. ^{[15
,16
,17
]}

Skieceviciene, Jurgita ^{[18
]}

Doncheva, Nadezhda T. ^{[19
]}

Liu, Xiao ^{[12
]}

Liu, Qing ^{[12
]}

Jiang, Fuman ^{[12
]}

Forster, Michael ^{[1
]}

Mayr, Gabriele ^{[19
]}

Albrecht, Mario ^{[19
,20
]}

Haesler, Robert ^{[1
]}

Boehm, Bernhard O. ^{[21
,22
]}

Goodall, Jane ^{[4
]}

Berzuini, Carlo R. ^{[5
]}

Lee, James ^{[3
]}

Andersen, Vibeke ^{[23
,24
]}

Vogel, Ulla ^{[25
]}

Kupcinskas, Limas ^{[18
]}

Kayser, Manfred ^{[26
]}

Krawczak, Michael ^{[2
,9
]}

Nikolaus, Susanna ^{[8
]}

Weersma, Rinse K. ^{[27
]}

Ponsioen, Cyriel Y. ^{[29
]}

Sans, Miquel ^{[30
]}

Wijmenga, Cisca ^{[28
]}

Strachan, David P. ^{[31
]}

McAardle, Wendy L. ^{[32
]}

Vermeire, Severine ^{[33
]}

Rutgeerts, Paul ^{[33
]}

Sanderson, Jeremy D. ^{[34
]}

Mathew, Christopher G. ^{[35
]}

Vatn, Morten H. ^{[36
]}

Wang, Jun ^{[12
]}

Noethen, Markus M. ^{[37
,38
]}

Duerr, Richard H. ^{[39
,40
]}

Buening, Carsten ^{[41
]}

Brand, Stephan ^{[42
]}

Glas, Juergen ^{[42
,43
,44
]}

Winkelmann, Juliane ^{[45
,47
,48
]}

Illig, Thomas ^{[46
,49
]}

Latiano, Anna ^{[50
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[2] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany

[3] Univ Cambridge, Addenbrookes Hosp, Gastroenterol Res Unit, Cambridge CB2 2QQ, England

[4] Univ Cambridge, Dept Med, Ctr Math Sci, Cambridge CB2 2QQ, England

[5] Univ Cambridge, Stat Lab, Ctr Math Sci, Cambridge CB2 1SB, England

[6] Sichuan Univ, West China Hosp, Dept Gastroenterol, Chengdu 610064, Peoples R China

[7] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610064, Peoples R China

[8] Univ Hosp Schleswig Holstein, Dept Internal Med, Kiel, Germany

[9] Univ Hosp Schleswig Holstein, PopGen Biobank, Kiel, Germany

[10] Univ Calif San Diego, Mol Biol Sect, La Jolla, CA 92093 USA

[11] San Diego Ctr Syst Biol, La Jolla, CA USA

[12] BGI Shenzhen, Shenzhen, Peoples R China

[13] Rutgers State Univ, Sch Environm & Biol Sci, Dept Biochem & Microbiol, New Brunswick, NJ 08903 USA

[14] Univ Saarland, Dept Human Genet, Homburg, Germany

[15] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[16] Broad Inst Harvard & MIT, Cambridge, MA USA

[17] Univ Oxford, Nuffield Dept Clin Med, Oxford, England

[18] Lithuanian Univ Hlth Sci, Inst Digest Res, Kaunas, Lithuania

[19] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[20] Univ Med Greifswald, Inst Biometr & Med Informat, Dept Bioinformat, Greifswald, Germany

[21] Univ Med Ctr Ulm, Dept Internal Med 1, Div Endocrinol & Diabet, Ulm, Germany

[22] Ctr Excellence Metab Disorders Baden Wurttemberg, Ulm, Germany

[23] Viborg Reg Hosp, Dept Med, Viborg, Denmark

[24] Aabenraa SHS, Dept Med, Aabenraa, Denmark

[25] Natl Res Ctr Working Environm, Copenhagen, Denmark

[26] Erasmus MC Univ, Med Ctr Rotterdam, Dept Forens Mol Biol, Rotterdam, Netherlands

[27] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol, NL-9713 AV Groningen, Netherlands

[28] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[29] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[30] Ctr Med Teknon, Serv Digest Dis, Barcelona, Spain

[31] Univ London, Div Populat Hlth Sci & Educ, London, England

[32] Univ Bristol, Dept Social & Community Med, Avon Longitudinal Study Parents & Children Lab, Bristol, Avon, England

[33] Univ Hosp Gasthuisberg, Div Gastroenterol, B-3000 Louvain, Belgium

[34] Guys & St Thomas Natl Hlth Serv Fdn Trust, Dept Gastroenterol, London, England

[35] Kings Coll London, Div Genet & Mol Med, London, England

[36] Univ Hosp, Rikshosp, Dept Med, Oslo, Norway

[37] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany

[38] Univ Bonn, Inst Human Genet, Bonn, Germany

[39] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[40] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[41] Charite, Dept Gastroenterol Hepatol & Endocrinol, Berlin, Germany

[42] Univ Munich, Dept Med 2, Munich, Germany

[43] Univ Munich, Dept Prevent Dent & Periodontol, Munich, Germany

[44] Rhein Westfal TH Aachen, Dept Human Genet, D-52062 Aachen, Germany

[45] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany

[46] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Res Unit Mol Epidemiol, Neuherberg, Germany

[47] Tech Univ Munich, MRI, Inst Human Genet, D-80290 Munich, Germany

[48] Tech Univ Munich, MRI, Dept Neurol, D-80290 Munich, Germany

[49] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany

[50] Casa Sollievo Sofferenza Hosp, Ist Ricovero & Cura Carattere Sci, Div Gastroenterol, San Giovanni Rotondo, Italy

来源：

GASTROENTEROLOGY | 2013年 / 145卷 / 02期

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金; 瑞典研究理事会;

关键词：

Inflammatory Bowel Disease; Whole-Exome Sequencing; Complex Disease; GENOME-WIDE ASSOCIATION; TRANSCRIPTIONAL REPRESSOR BLIMP-1; INFLAMMATORY-BOWEL-DISEASE; T-CELL HOMEOSTASIS; SUSCEPTIBILITY LOCI; LYMPHOCYTE MIGRATION; ULCERATIVE-COLITIS; AUTOPHAGY RECEPTOR; L-SELECTIN; EXPRESSION;

D O I：

10.1053/j.gastro.2013.04.040

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B 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.

引用

页码：339 / 347

页数：9

共 33 条

[11] Genetic Variation in the Autophagy Gene ULK1 and Risk of Crohn's Disease [J].

Henckaerts, Liesbet ;

Cleynen, Isabelle ;

Brinar, Marko ;

John, Jestinah Mahachie ;

Van Steen, Kristel ;

Rutgeerts, Paul ;

Vermeire, Severine .

INFLAMMATORY BOWEL DISEASES, 2011, 17 (06) :1392-1397

[12] Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20 [J].

Inomata, Megumi ;

Niida, Shumpei ;

Shibata, Ken-ichiro ;

Into, Takeshi .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2012, 69 (06) :963-979

[13] NDP52: the missing link between ubiquitinated bacteria and autophagy [J].

Ivanov, Stanimir ;

Roy, Craig R. .

NATURE IMMUNOLOGY, 2009, 10 (11) :1137-1139

[14] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease [J].

Jostins, Luke ;

Ripke, Stephan ;

Weersma, Rinse K. ;

Duerr, Richard H. ;

McGovern, Dermot P. ;

Hui, Ken Y. ;

Lee, James C. ;

Schumm, L. Philip ;

Sharma, Yashoda ;

Anderson, Carl A. ;

Essers, Jonah ;

Mitrovic, Mitja ;

Ning, Kaida ;

Cleynen, Isabelle ;

Theatre, Emilie ;

Spain, Sarah L. ;

Raychaudhuri, Soumya ;

Goyette, Philippe ;

Wei, Zhi ;

Abraham, Clara ;

Achkar, Jean-Paul ;

Ahmad, Tariq ;

Amininejad, Leila ;

Ananthakrishnan, Ashwin N. ;

Andersen, Vibeke ;

Andrews, Jane M. ;

Baidoo, Leonard ;

Balschun, Tobias ;

Bampton, Peter A. ;

Bitton, Alain ;

Boucher, Gabrielle ;

Brand, Stephan ;

Buening, Carsten ;

Cohain, Ariella ;

Cichon, Sven ;

D'Amato, Mauro ;

De Jong, Dirk ;

Devaney, Kathy L. ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Ellinghaus, David ;

Ferguson, Lynnette R. ;

Franchimont, Denis ;

Fransen, Karin ;

Gearry, Richard ;

Georges, Michel ;

Gieger, Christian ;

Glas, Juergen ;

Haritunians, Talin ;

Hart, Ailsa .

NATURE, 2012, 491 (7422) :119-124

[15] Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance [J].

Kallies, A ;

Hawkins, ED ;

Belz, GT ;

Metcalf, D ;

Hommel, M ;

Corcoran, LM ;

Hodgkin, PD ;

Nutt, SL .

NATURE IMMUNOLOGY, 2006, 7 (05) :466-474

[16] MOLECULAR CHARACTERIZATION OF NDP52, A NOVEL PROTEIN OF THE NUCLEAR DOMAIN-10, WHICH IS REDISTRIBUTED UPON VIRUS-INFECTION AND INTERFERON TREATMENT [J].

KORIOTH, F ;

GIEFFERS, C ;

MAUL, GG ;

FREY, J .

JOURNAL OF CELL BIOLOGY, 1995, 130 (01) :1-13

[17] Finding the missing heritability of complex diseases [J].

Manolio, Teri A. ;

Collins, Francis S. ;

Cox, Nancy J. ;

Goldstein, David B. ;

Hindorff, Lucia A. ;

Hunter, David J. ;

McCarthy, Mark I. ;

Ramos, Erin M. ;

Cardon, Lon R. ;

Chakravarti, Aravinda ;

Cho, Judy H. ;

Guttmacher, Alan E. ;

Kong, Augustine ;

Kruglyak, Leonid ;

Mardis, Elaine ;

Rotimi, Charles N. ;

Slatkin, Montgomery ;

Valle, David ;

Whittemore, Alice S. ;

Boehnke, Michael ;

Clark, Andrew G. ;

Eichler, Evan E. ;

Gibson, Greg ;

Haines, Jonathan L. ;

Mackay, Trudy F. C. ;

McCarroll, Steven A. ;

Visscher, Peter M. .

NATURE, 2009, 461 (7265) :747-753

[18] Transcriptional repressor Blimp-1 regulates T cell homeostasis and function [J].

Martins, GA ;

Cimmino, L ;

Shapiro-Shelef, M ;

Szabolcs, M ;

Herron, A ;

Magnusdottir, E ;

Calame, K .

NATURE IMMUNOLOGY, 2006, 7 (05) :457-465

[19] Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease [J].

McCarroll, Steven A. ;

Huett, Alan ;

Kuballa, Petric ;

Chilewski, Shannon D. ;

Landry, Aimee ;

Goyette, Philippe ;

Zody, Michael C. ;

Hall, Jennifer L. ;

Brant, Steven R. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Rioux, John D. ;

Altshuler, David ;

Daly, Mark J. ;

Xavier, Ramnik J. .

NATURE GENETICS, 2008, 40 (09) :1107-1112

[20] T6BP and NDP52 are myosin VI binding partners with potential roles in cytokine signalling and cell adhesion [J].

Morriswood, Brooke ;

Ryzhakov, Grigory ;

Puri, Claudia ;

Arden, Susan D. ;

Roberts, Rhys ;

Dendrou, Calliope ;

Kendrick-Jones, John ;

Buss, Folma .

JOURNAL OF CELL SCIENCE, 2007, 120 (15) :2574-2585

← 1 2 3 4 →