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Celiac Disease First: Researchers Identify a Role for Main Inherited Genetic Variation

Celiac.com 08/20/2009 - For the first time, a team of celiac disease researchers has discovered a role for the main inherited celiac-associated genetic variation, connecting altered NF-kB signalling with risk variants associated with Celiac disease in TNFAIP3 and REL.

The research team was made up of G. Trynka, A. Zhernakova, J. Romanos, L. Franke, K. A. Hunt, G. Turner, M. Bruinenberg, G. A. Heap, M. Platteel,1 A. W. Ryan, C. de Kovel, G. K. T. Holmes, P. D. Howdle, J. R. F. Walters, D. S. Sanders, C. J. J. Mulder, M. L. Mearin, W. H. M. Verbeek, V. Trimble, F. M. Stevens, D. Kelleher, D. Barisani, M. T. Bardella, R. McManus, D. A. van Heel, C. Wijmenga.

An earlier celiac disease genome-wide association study (GWAS) identified risk variants in the human leucocyte antigen (HLA) region and eight new risk areas.

To find more celiac disease locations, the research team chose to examine 458 single nucleotide polymorphisms (SNPs) that exhibited weaker ties in the GWAS for genotyping and analysis in four independent cohorts. The 458 SNPs were found among 1682 cases and 3258 controls from UK, Irish and Dutch populations.

The team combined the results with the original GWAS cohort involving 767 UK cases and 1422 controls), in which six SNPs showed association with p,1610. Those six were then genotyped in an independent Italian celiac cohort (538 cases and 593 controls). The research team found two new celiac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL).

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In the final combined analysis of all 2987 cases and 5273 controls, both regions achieved genome-wide significance (rs2327832 p=1.3610, and rs842647 p=5.2610).

The researchers used RNA isolated from biopsies and from whole
blood RNA to look at gene expression. They observed no changes in either gene expression, or in the correlation of genotype with gene expression.

From these results, the research team concluded that both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kB) inflammatory signalling pathway.

For the first time, researchers have identified a role for main inherited variation in this important biological pathway that predisposes individuals to celiac disease.

Currently, the HLA risk factors and the 10 established non-HLA risk factors provide an explanation for about 40% of inheritance factors for celiac disease.

Clearly, more research is needed to isolate the other 60% of inheritability factors for celiac disease. Success in this very important area promises to open up the understanding of celiac disease, and to help speed new treatments, and possibly a cure.


Gut 2009;58:1078–1083.

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We have gone gluten free, our whole house, as of a month ago. It was pretty seamless since I had been gluten-free for 5 months last year. I have found many good recipes, and my picky husband and one of my boys who is also a picky eater, even prefer many gluten-free recipes to the regular ones. My husband did see my point about the size of the gluten protein means nothing. Its a gluten protein period, that's what you are avoiding. It doesn't matter if its hiding in the scratch of your baking sheet and you can't see it. You can't see the wind, but it's still there. I hear you on the anemia. I've been anemic for several years, I just thought it as because I was getting a little older. Has your anemia gone away or do you still have problems with it?

Ennis, it is made out of metal, coated with plastic I think. You have such a hard time, my heart really hurts for you. But you are such a support to those on this board, and a great teacher for those of us who are new.

Thanks everyone! I think its hard for people to fully accept because they cant see the damage it does every time you get glutened. It's invisible. Im glad to know I wasnt being paranoid. I sure was when I was first diagnosed. I laugh at myself now, but its a pretty steep learning curve.

FYI......anxiety is a common symptom with celiac disease and NCGI. It seems to resolve on a gluten-free diet. ?

Yes, I will definitely update you and would love to hear what your experience is. I'm glad I found this forum because you're right--it's nice to not feel so alone. I'm also prone to anxiety--so waiting and worrying is not fun! Cyclinglady, thanks for sharing your experience as well. I do plan to maintain a gluten-free diet for a while at least if the biopsy is negative just to see how I feel.