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Jefferson Adams posted an article in Diabetes and Celiac DiseaseCeliac.com 02/28/2018 - In an effort to discover more genes that trigger type 1 diabetes, a team of researchers recently conducted a large, prospective study of children at risk for type 1 diabetes. The end goal is to reveal more targets for treating or even preventing the disease. The research team included A Sharma, X Liu, D Hadley, W Hagopian, WM Chen, S Onengut-Gumuscu, C Törn, AK Steck, BI Frohnert, M Rewers, AG Ziegler, Å Lernmark, J Toppari, JP Krischer, B Akolkar, SS Rich, JX She; and TEDDY Study Group. The team identified six new chromosomal regions in young people who have already developed type 1 diabetes, or who have started making antibodies against their insulin-producing cells, often a step toward full-blown diabetes that requires lifelong insulin therapy. Their analysis of 5,806 individuals, which is published in the Journal of Autoimmunity, also confirms three regions already associated with one of those related conditions. The team observed two top autoantibodies. The first, called IAA, acts directly against insulin. The second, called GADA, acts against the enzyme glutamate decarboxylase, which regulates the insulin-producing beta cells in the pancreas. According to Dr. She, about 90 percent of patients with type 1 diabetes start with one of the autoantibodies, and many patients eventually end up with both. The second autoantibody may surface in a few days or even years later. They began this study with 176,586 SNPs, or single nucleotide polymorphisms. Nucleotides are basic building blocks of our genetic information. According to Sharma, the SNPs evaluated by TEDDY scientists were already linked with other autoimmune conditions like rheumatoid arthritis or celiac disease, but not type 1 diabetes. The researchers figured out which of these SNPs are different in TEDDY participants with type 1 diabetes versus those with Islet cell autoantibodies versus those with neither. Previous research has shown that the genes associated with IA and actual type 1 diabetes can differ. Dr. She says that even though clinicians regard Islet cell autoantibodies (IA) as a red flag for type 1 diabetes, not every child with IA goes on to develop diabetes, though multiple autoantibodies definitely increase that risk. The team notes that it is possible that the genes that promote IA development may differ from those that lead to full-blown disease progression. She says that this is the first study of gene identification for any disease to use this sort of longitudinal information. She add that this and other studies by the TEDDY research group help to clarify the search for important non-HLA genes by adding the "time to disease" perspective. Source: J Autoimmun. 2018 Jan 5. pii: S0896-8411(17)30739-4. doi: 10.1016/j.jaut.2017.12.008. The researchers are variously affiliated with the Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Division of Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA, US; the Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; the Division of Population Health Sciences and Education, St George's University of London, London, United Kingdom; the Pacific Northwest Research Institute, Seattle, WA, USA; the Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; the Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden; the Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO, USA; the Institute of Diabetes Research, Helmholtz Zentrum München, Munich-Neuherberg, Germany; Klinikum rechts der Isar, Technische Universität München, Munich-Neuherberg, Germany; Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany; the Department of Pediatrics, Turku University Hospital, Turku, Finland; the National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, USA; and the Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Scott Adams posted an article in Celiac Disease Diagnosis, Testing & TreatmentDig Dis Sci 1999;44:2344-2349. Celiac.com 04/10/2000 - Dr. Carme Farre, of Hospital Sant Joan de Deu, in Barcelona, Spain, and his multi-center colleagues, report in the November issue of Digestive Diseases and Sciences that both serologic markers and the human lymphocyte antigen class II extended DQ2 (HLA-DQ2) haplotype are useful markers for screening first-degree relatives of patients with celiac disease for the disorder. These markers are more reliable predictors of celiac disease than other clinical features, which are absent from one third of relatives of people with celiac disease. The researchers examined the usefulness of serologic markers, HLA-DQ2 haplotype, and clinical features common to celiac disease in the diagnosis of the disorder in 675 first-degree relatives of celiac disease patients. The diagnosis was confirmed by intestinal biopsy. Their results showed that 5.5% of the subjects were diagnosed with celiac disease, which is significantly higher than what was observed in the general public in a previous study. Serum IgA-class anti-endomysium antibodies (IgA-AEA) and IgA-class anti-gliadin antibodies (IgA-AGA) were observed in 5.8% and 1.9% of the relatives, respectively. According to the researchers: Our results show that IgA-AEA is the most useful marker, since all but one IgA-AEA-positive relative showed histological findings of [celiac disease]. Further, the measurement of IgA-AGA would have missed 66% of the affected relatives. The researchers also concluded that the HLA-DQ2 haplotype also appeared to be a more useful indicator to determine which first-degree relatives had an increased genetic susceptibility to celiac disease, because the marker was detected in 93% of first-degree relatives found to have celiac disease, and 18% of those without it. The four most common clinical symptoms for celiac disease, diarrhea, anemia, food intolerance and growth retardation, were not found in one third of the relatives of patients with celiac disease. The researchers conclude: Although the definitive diagnosis of [celiac disease] relies upon the intestinal biopsy, it should be preceded by a noninvasive, inexpensive and easy-to-perform screening technique. Their findings indicate that using blood serum IgA-AEA measurements is a useful screening tool for noninvasive screening, and HLA-DQ2 assessment may delineate a very high risk population with a particular genetic susceptibility to [celiac disease].
Jefferson Adams posted an article in Refractory Celiac Disease & Collagenous SprueCeliac.com 09/21/2012 - Refractory celiac disease type II (RCDII) is a severe complication of celiac disease that occurs when symptoms and intestinal damage continue even when the patient adopt a gluten-free diet. Refractory celiac disease marked by abnormal intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3(-)CD7(+)icCD3(+) phenotype. About 40% of patients with RCDII lymphocytes develop a dangerous and invasive lymphoma. A team of researchers recently sought to identify possible origins of abnormal intraepithelial lymphocytes in refractory celiac disease type II. The research team included F. Schmitz; T.M. Tjon, Y. Lai; A. Thompson; Y. Kooy-Winkelaar; R.J. Lemmers; H.W. Verspaget; M.L. Mearin; F.J. Staal; M.W. Schreurs; T. Cupedo; A.W. Langerak; C.J. Mulder; J. van Bergen; and F. Koning. In their study, the researches sought to find the physiological counterpart of these abnormal intraepithelial lymphocytes cells. To do so, they used microarray analysis, real-time quantitative PCR and flow cytometry to compare RCDII cell lines with T-cell receptor positive (TCR(+)) IEL (T-IEL) lines. They then used their data to identify cells with an RCDII-associated phenotype in duodenal biopsies from non-refractory individuals by multicolor flow cytometry. They found that RCDII cell lines were distinct from T-IEL lines and showed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3(-)CD7(+)icCD3(+) phenotype, the RCDII lines showed an absence of CD56, CD127 and CD34, compared with other lymphocyte subsets. Moreover, they found cells matching this surface lineage-negative (Lin(-)) CD7(+)CD127(-)CD34(-) phenotype that showed a functional interleukin-15 (IL-15) receptor and comprised a substantial portion of IELs in duodenal specimens of patients without celiac disease, particularly children. They also found cells of this kind in the thymus. For patients without celiac disease, the Lin(-)CD7(+)CD127(-)CD34(-) subset was one of four subsets within the CD3(-)CD7(+)icCD3(+) population that showed a differential expression of CD56 and/or CD127. The results indicate that the CD3(-)CD7(+)icCD3(+) population is heterogeneous and show the existence of a Lin(-) subset that is different from T, B, NK and lymphoid tissue inducer cells. The team hypothesizes that the IL-15 cells are the counterpart of abnormal cells that are expanded in RCDII and transformed in RCDII-associated lymphoma. Source: Gut. 2012 Jul 6.
Jefferson Adams posted an article in Celiac Disease & Gluten Intolerance ResearchCeliac.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.