RT Journal Article
SR Electronic
T1 Coeliac disease-associated risk variants in <em>TNFAIP3</em> and <em>REL</em> implicate altered NF-κB signalling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1078
OP 1083
DO 10.1136/gut.2008.169052
VO 58
IS 8
A1 G Trynka
A1 A Zhernakova
A1 J Romanos
A1 L Franke
A1 K A Hunt
A1 G Turner
A1 M Bruinenberg
A1 G A Heap
A1 M Platteel
A1 A W Ryan
A1 C de Kovel
A1 G K T Holmes
A1 P D Howdle
A1 J R F Walters
A1 D S Sanders
A1 C J J Mulder
A1 M L Mearin
A1 W H M Verbeek
A1 V Trimble
A1 F M Stevens
A1 D Kelleher
A1 D Barisani
A1 M T Bardella
A1 R McManus
A1 D A van Heel
A1 C Wijmenga
YR 2009
UL http://gut.bmj.com/content/58/8/1078.abstract
AB 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&lt;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.