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  • Jefferson Adams
    Jefferson Adams

    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).

    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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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Scott Adams
    Paul V, Henkerr J, Todt H, Eysold R.
    Z.Klin.Med., 1985; 40: 707-709.
    In this study 90 EEGs were performed on 58 celiac children. Researchers concluded that abnormal brain waves resulted from the ingestion of gluten by celiac children. They also concluded that a gluten challenge should not be given before a child reaches the age of 6 years old, and the challenge should not last longer than 5 months. The researchers main concern seems to be the risk of permanent brain damage that they believe could be caused in a celiac child who eats gluten for a prolonged period of time.

    Jefferson Adams
    UK Study: Mortality for Untreated Celiac Disease Same as General Population
    Celiac.com 09/29/2011 - Results of various studies comparing mortality in undetected celiac disease compared with the general population have been contradictory. Some studies have suggested a fourfold increase in mortality compared with the general population, while others have found no increase at all.
    A research team set out to clarify the matter by crafting a cohort study of Cambridge doctors that would establish all-cause and cause-specific mortality in undiagnosed celiac disease, identified by anti-endomysial antibody (EMA) positivity.
    The team included C. Canavan, R. F. Logan, K. T. Khaw, and J. West. They are variously affiliated with the Division of Epidemiology and Public Health at University of Nottingham in Nottingham, UK, with the NIHR Biomedical Research Unit of the Nottingham Digestive Diseases Centre at Nottingham University Hospital in Nottingham, UK, and with the Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    For their study, the team chose their subjects from a general population aged 45-76 years in 1990.
    They then tracked all deaths using the Office for National Statistics. They calculated mortality rates per 1000 person year, making adjustments for age, gender, smoking and socioeconomic group using multivariate Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI).
    Results showed 117,914 patient years of follow-up from 7527 participants, with an average of 16.8 years.
    Eighty-seven patients suffered from undetected celiac disease, their all-cause mortality rate was 9.4 per 1000 person years (95% CI 5.4-16.1) compared with 12.7 (95% CI 12.1-13.4) in EMA-negative participants.
    The adjusted all-cause mortality hazard ratio was 0.98 (95% CI 0.57-1.69). Untreated celiac disease showed no increase in death due to cancer or circulatory diseases. Adjusted hazard ratios were 1.27 (95% CI 0.57-2.85) and 1.39 (95% CI 0.66-2.92) respectively.
    The research team found no higher overall mortality in people older than 45 years with undetected coeliac disease compared with the general population. They also found no increase in deaths related to circulatory disease or cancer.
    The team concludes that these results do not support routine screening people older than 45 years for celiac disease.
    Source:

     Aliment Pharmacol Ther. 2011 Aug 17. doi: 10.1111/j.1365-2036.2011.04811.x.

    Jefferson Adams
    Influence of HLA-DQ2 and DQ8 on Severity in Celiac Disease
    Celiac.com 03/14/2012 - A group of researchers recently studied the ways in which HLA-DQ2 and DQ8 might influence the severity of celiac disease. Specifically, the team wanted to study HLA-DQA1 and DQB1 profiles in adults with different forms of celiac disease, including adults with complicated and potential celiac disease, the most seriously affected, and those with the best preserved histologic end of the pathologic celiac spectrum.
    The researchers included F. Biagi, P.I. Bianchi, C. Vattiato, A. Marchese, L. Trotta, C. Badulli, A. De Silvestri, M. Martinetti, and G.R. Corazza. They are affiliated with the Coeliac Centre/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy. 
    Patients with complicated celiac disease showed more HLA-DQB1*02 homozygosity than those with uncomplicated celiac disease.
    The team conducted HLA-DQA1 and DQB1 molecular typing for 218 adults with celiac disease. Of these, 169 had uncomplicated celiac disease, 27 had complicated celiac disease, and 22 had potential celiac disease. They used 224 healthy stem cell donors as a control group.
    The team analyzed HLA-DQA1 and DQB1 gene polymorphism using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides. They found, as expected, that the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the four groups.
    However, multivariate analysis showed that patients with potential celiac disease have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles, along with a reduced frequency of DQB1*02 homozygosity, as compared with patients with uncomplicated and complicated celiac disease.
    The increased frequency of DQB1*0302 coupled with the reduced frequency of DQB1*02 homozygosity in potential celiac disease supports the idea that variations in clinical/pathologic expressions of celiac disease might reflect different immune system triggers. This observation could impact the way in which celiac disease is understood and studied in the future.
    Source:

    J Clin Gastroenterol. 2012 Jan;46(1):46-50.

    Jefferson Adams
    Celiac.com 10/03/2014 - Celiac disease patients in Australia have shown a major improvement in gluten tolerance after receiving experimental hookworm treatments. The study is part of an effort to determine if parasitic helminths, such as hookworm, might help to treat inflammatory disorders, including celiac disease.
    In this case, the research team assessed the influence of experimental hookworm infection on the predicted outcomes of three escalating gluten challenges in volunteers with confirmed celiac disease.
    The research team included John Croese, MD, Paul Giacomin, PhD, Severine Navarro, PhD, Andrew Clouston, MD, Leisa McCann, RN, Annette Dougall, PhD, Ivana Ferreira, BSc, Atik Susianto, MD, Peter O'Rourke, PhD, Mariko Howlett, MD, James McCarthy, MD, Christian Engwerda, PhD, Dianne Jones, BHSc, and Alex Loukas, PhD.
    They are variously affiliated with the Department of Gastroenterology and Hepatology at The Prince Charles Hospital, Brisbane, Australia, the Center for Biodiscovery and Molecular Development of Therapeutics at the Australian Institute of Tropical Health and Medicine of James Cook University in Cairns, Australia, Envoi Specialist Pathologists in Brisbane, Australia, QIMR Berghofer Medical Research Institute in Brisbane, Australia, the Royal Brisbane and Women's Hospital, and with Logan Hospital, Brisbane, Australia.
    This particular study followed twelve adult volunteers with diet-managed celiac disease. The volunteers were inoculated with 20 Necator americanus (hookworm) larvae, and then consumed increasing amounts of gluten in the form of spaghetti.
    The volunteers first received 10 to 50 milligrams for 12 weeks (microchallenge); they then received 25 milligrams daily + 1 gram twice weekly for 12 weeks (GC-1g); and finally 3 grams daily (60-75 straws of spaghetti) for 2 weeks (GC-3g).
    The subjects were then evaluated for symptomatic, serologic, and histological outcomes of gluten toxicity. They were also examined for regulatory and inflammatory T cell populations in blood and mucosa. Two gluten-intolerant subjects withdrew after micro-challenge. Ten completed GC-1g, and eight of these ten volunteers enrolled in and completed the full course of the study.
    Most celiacs who are exposed to gluten challenge will show adverse changes in the intestinal villi, which is measured in terms of villous height-to-crypt depth ratios. Also, such patients will usually show an increase in blood antibodies, such as IgA-tissue transglutaminase, indiucating an adverse reaction to gluten. However, the results here showed that median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g. Moreover, mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g.
    Other results showed that quality of life scores improved (46.3-40.6; P = .05); while celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores remained unchanged by gluten challenge.
    Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4+ Foxp3+ regulatory T cells (0.19%-1.12%; P = .001).
    Hookworms in the form of Necator americanus promoted tolerance and stabilized, or improved, all tested measures of gluten toxicity in volunteers with celiac disease. So, after being voluntarily infected with 20 hookworms, these celiac disease volunteers were able to eat increasingly large amounts of gluten with none of the usual changes or adverse symptoms.
    Could hookworm treatments represent the future of treatment for celiac disease, and maybe other inflammatory conditions? Clearly, further tests are needed to determine exactly how safe it is for celiac patients receiving this treatment to eat gluten. So far, however, the future looks bright.
    What do you think? If swallowing a small dose of hookworms would eliminate your adverse reactions, and allow you to safely eat gluten, would you do it?
    The radio program Radiolab has an interesting segment on hookworm, which you can stream here: Radiolab
    Source:
    Journal of Allergy and Clinical Immunology. DOI: http://dx.doi.org/10.1016/j.jaci.2014.07.022

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    Im the same, I never know what to eat, some food does better than others for me, I went on to make my own soup and Im glad I did, I should do it more often and at least then J know what's going in to it, it wasn't the best first try but I enjoyed it haha
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