Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling

被引：146

作者：

Trynka, G. ^{[1
,2
]}

Zhernakova, A. ^{[3
]}

Romanos, J. ^{[1
,2
]}

Franke, L. ^{[1
,2
,4
]}

Hunt, K. A. ^{[4
]}

Turner, G. ^{[5
]}

Bruinenberg, M. ^{[1
,2
]}

Heap, G. A. ^{[4
]}

Platteel, M. ^{[1
,2
]}

Ryan, A. W. ^{[5
]}

de Kovel, C. ^{[3
]}

Holmes, G. K. T. ^{[6
]}

Howdle, P. D. ^{[7
]}

Walters, J. R. F. ^{[8
]}

Sanders, D. S. ^{[9
,10
]}

Mulder, C. J. J. ^{[11
]}

Mearin, M. L. ^{[12
]}

Verbeek, W. H. M. ^{[11
]}

Trimble, V. ^{[5
]}

Stevens, F. M. ^{[13
]}

Kelleher, D. ^{[5
]}

Barisani, D. ^{[14
]}

Bardella, M. T. ^{[15
,16
]}

McManus, R. ^{[5
]}

van Heel, D. A. ^{[4
]}

Wijmenga, C. ^{[1
,2
,3
]}

机构：

[1] Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[2] Univ Groningen, NL-9700 RB Groningen, Netherlands

[3] Univ Med Ctr Utrecht, Dept Biomed Genet, Complex Genet Sect, Utrecht, Netherlands

[4] Barts & London Queen Marys Sch Med & Dent, Inst Cell & Mol Sci, London, England

[5] Trinity Coll Dublin, Dept Clin Med, Inst Mol Med, Dublin, Ireland

[6] Derbyshire Royal Infirm, Dept Gastroenterol, Derby DE1 2QY, England

[7] St James Univ Hosp, Acad Med Unit, Leeds Inst Mol Med, Leeds, W Yorkshire, England

[8] Univ London Imperial Coll Sci Technol & Med, Gastroenterol Sect, Hammersmith Hosp, London, England

[9] Royal Hallamshire Hosp, Dept Gastroenterol, Sheffield S10 2JF, S Yorkshire, England

[10] Royal Hallamshire Hosp, Liver Unit, Sheffield S10 2JF, S Yorkshire, England

[11] VU Med Ctr, Dept Gastroenterol, Amsterdam, Netherlands

[12] Leiden Univ, Med Ctr, Dept Paediat Gastroenterol, Leiden, Netherlands

[13] Natl Univ Ireland, Dept Med, Galway, Ireland

[14] Univ Milan, Fac Med, Dept Expt Med, Monza, Italy

[15] Osped Maggiore Policlin, Fdn IRCCS, Milan, Italy

[16] Univ Milan, Dept Med Sci, I-20122 Milan, Italy

来源：

GUT | 2009年 / 58卷 / 08期

基金：

英国惠康基金; 爱尔兰科学基金会;

关键词：

GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; IMMUNE-RESPONSE; A20; REGION; 6Q23; INFLAMMATION;

D O I：

10.1136/gut.2008.169052

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1x10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p= 1.3x10(-08), and rs842647 p= 5.26x10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappa B) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain similar to 40% of the heritability of coeliac disease.

引用

页码：1078 / 1083

页数：6

共 26 条

[1] Haploview: analysis and visualization of LD and haplotype maps [J].

Barrett, JC ;

Fry, B ;

Maller, J ;

Daly, MJ .

BIOINFORMATICS, 2005, 21 (02) :263-265

[2] The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses [J].

Boone, DL ;

Turer, EE ;

Lee, EG ;

Ahmad, RC ;

Wheeler, MT ;

Tsui, C ;

Hurley, P ;

Chien, M ;

Chai, S ;

Hitotsumatsu, O ;

McNally, E ;

Pickart, C ;

Ma, A .

NATURE IMMUNOLOGY, 2004, 5 (10) :1052-1060

[3] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[4] A20: Central Gatekeeper in Inflammation and Immunity [J].

Coornaert, Beatrice ;

Carpentier, Isabelle ;

Beyaert, Rudi .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (13) :8217-8221

[5] A genome-wide association study of global gene expression [J].

Dixon, Anna L. ;

Liang, Liming ;

Moffatt, Miriam F. ;

Chen, Wei ;

Heath, Simon ;

Wong, Kenny C. C. ;

Taylor, Jenny ;

Burnett, Edward ;

Gut, Ivo ;

Farrall, Martin ;

Lathrop, G. Mark ;

Abecasis, Goncalo R. ;

Cookson, William O. C. .

NATURE GENETICS, 2007, 39 (10) :1202-1207

[6] Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus [J].

Graham, Robert R. ;

Cotsapas, Chris ;

Davies, Leela ;

Hackett, Rachel ;

Lessard, Christopher J. ;

Leon, Joanlise M. ;

Burtt, Noel P. ;

Guiducci, Candace ;

Parkin, Melissa ;

Gates, Casey ;

Plenge, Robert M. ;

Behrens, Timothy W. ;

Wither, Joan E. ;

Rioux, John D. ;

Fortin, Paul R. ;

Graham, Deborah Cunninghame ;

Wong, Andrew K. ;

Vyse, Timothy J. ;

Daly, Mark J. ;

Altshuler, David ;

Moser, Kathy L. ;

Gaffney, Patrick M. .

NATURE GENETICS, 2008, 40 (09) :1059-1061

[7] Complex nature of SNP genotype effects on gene expression in primary human leucocytes [J].

Heap, Graham A. ;

Trynka, Gosia ;

Jansen, Ritsert C. ;

Bruinenberg, Marcel ;

Swertz, Morris A. ;

Dinesen, Lotte C. ;

Hunt, Karen A. ;

Wijmenga, Cisca ;

vanHeel, David A. ;

Franke, Lude .

BMC MEDICAL GENOMICS, 2009, 2

[8] Newly identified genetic risk variants for celiac disease related to the immune response [J].

Hunt, Karen A. ;

Zhernakova, Alexandra ;

Turner, Graham ;

Heap, Graham A. R. ;

Franke, Lude ;

Bruinenberg, Marcel ;

Romanos, Jihane ;

Dinesen, Lotte C. ;

Ryan, Anthony W. ;

Panesar, Davinder ;

Gwilliam, Rhian ;

Takeuchi, Fumihiko ;

McLaren, William M. ;

Holmes, Geoffrey K. T. ;

Howdle, Peter D. ;

Walters, Julian R. F. ;

Sanders, David S. ;

Playford, Raymond J. ;

Trynka, Gosia ;

Mulder, Chris J. J. ;

Mearin, M. Luisa ;

Verbeek, Wieke H. M. ;

Trimble, Valerie ;

Stevens, Fiona M. ;

O'Morain, Colm ;

Kennedy, Nicholas P. ;

Kelleher, Dermot ;

Pennington, Daniel J. ;

Strachan, David P. ;

McArdle, Wendy L. ;

Mein, Charles A. ;

Wapenaar, Martin C. ;

Deloukas, Panos ;

McGinnis, Ralph ;

McManus, Ross ;

Wijmenga, Cisca ;

van Heel, David A. .

NATURE GENETICS, 2008, 40 (04) :395-402

[9] Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice [J].

Lee, EG ;

Boone, DL ;

Chai, S ;

Libby, SL ;

Chien, M ;

Lodolce, JP ;

Ma, A .

SCIENCE, 2000, 289 (5488) :2350-2354

[10] Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus [J].

Musone, Stacy L. ;

Taylor, Kimberly E. ;

Lu, Timothy T. ;

Nititham, Joanne ;

Ferreira, Ricardo C. ;

Ortmann, Ward ;

Shifrin, Nataliya ;

Petri, Michelle A. ;

Kamboh, M. Ilyas ;

Manzi, Susan ;

Seldin, Michael F. ;

Gregersen, Peter K. ;

Behrens, Timothy W. ;

Ma, Averil ;

Kwok, Pui-Yan ;

Criswell, Lindsey A. .

NATURE GENETICS, 2008, 40 (09) :1062-1064

← 1 2 3 →