Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling
- G Trynka1,
- A Zhernakova2,
- J Romanos1,
- L Franke1,3,
- K A Hunt3,
- G Turner4,
- M Bruinenberg1,
- G A Heap3,
- M Platteel1,
- A W Ryan4,
- C de Kovel2,
- G K T Holmes5,
- P D Howdle6,
- J R F Walters7,
- D S Sanders8,
- C J J Mulder9,
- M L Mearin10,
- W H M Verbeek9,
- V Trimble4,
- F M Stevens11,
- D Kelleher4,
- D Barisani12,
- M T Bardella13,14,
- R McManus4,
- D A van Heel3,
- C Wijmenga1,2
- 1Genetics Department, University Medical Centre and University of Groningen, The Netherlands
- 2Complex Genetics Section, Department of Biomedical Genetics, University Medical Centre Utrecht, The Netherlands
- 3Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK
- 4Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Ireland
- 5Department of Gastroenterology, Derbyshire Royal Infirmary, Derby, UK
- 6Academic Medical Unit, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK
- 7Gastroenterology Section, Imperial College London, Hammersmith Hospital, London, UK
- 8Department of Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield, UK
- 9Department of Gastroenterology, VU Medical Center, Amsterdam, The Netherlands
- 10Department of Paediatric Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
- 11Department of Medicine, National University of Ireland, Galway, Ireland
- 12Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Monza, Italy
- 13Fondizione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
- 14Department of Medical Sciences, University of Milan, Italy
- Professor C Wijmenga, Department of Genetics, University Medical Centre Groningen and University of Groningen, Internal post HPC CB50, PO Box 30001, 9700 RB Groningen, The Netherlands;
- Revised 6 February 2009
- Accepted 12 February 2009
- Published Online First 24 February 2009
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<1×10−04 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 = 1.3×10−08, and rs842647 p = 5.2×10−07). 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-κB) 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 ∼40% of the heritability of coeliac disease.
Competing interests: None.
Funding: The study was supported by grants from Coeliac UK (to DAvH); the Coeliac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to CW); the European Union (STREP 036383); the Netherlands Organization for Scientific Research (VICI grant 918.66.620 to CW); the Science Foundation Ireland; the Higher Education Authority PRTLI; The Irish Health Research Board; and the Wellcome Trust (GR068094MA Clinician Scientist Fellowship to DAvH; New Blood Fellowship to RMcM).
Ethics approval: Ethics approval was from Oxfordshire REC B or East London and the City REC 1 (UKGWAS, UK2), the Medical Ethical Committee of the University Medical Centre Utrecht (Dutch), the Institutional Ethics Committee of St James’s Hospital (Irish) and the Ethics Committee of the Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena (Italian).
▸ Two supplementary files giving additional data for the SNPs in this study are published online only at http://gut.bmj.com/content/vol58/issue8