Small intestine

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

G Trynka¹, A Zhernakova², J Romanos¹, L Franke^1,3, 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 Bardella^13,14, R McManus⁴, D A van Heel³, C Wijmenga^1,2

¹ Genetics Department, University Medical Centre and University of Groningen, The Netherlands
² Complex Genetics Section, Department of Biomedical Genetics, University Medical Centre Utrecht, The Netherlands
³ Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK
⁴ Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Ireland
⁵ Department of Gastroenterology, Derbyshire Royal Infirmary, Derby, UK
⁶ Academic Medical Unit, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK
⁷ Gastroenterology Section, Imperial College London, Hammersmith Hospital, London, UK
⁸ Department of Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield, UK
⁹ Department of Gastroenterology, VU Medical Center, Amsterdam, The Netherlands
¹⁰ Department of Paediatric Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
¹¹ Department of Medicine, National University of Ireland, Galway, Ireland
¹² Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Monza, Italy
¹³ Fondizione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
¹⁴ Department 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; c.wijmenga{at}umcutrecht.nl

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 = 5.2x10^–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-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 40% of the heritability of coeliac disease.

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