Titel Deelnemers "Korte inhoud" "Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol" "Kristina Casteels" "INTRODUCTION: The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes. METHODS AND ANALYSIS: Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes. ETHICS AND DISSEMINATION: The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. TRIAL REGISTRATION NUMBER: NCT03364868." "Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results" "Christiane Winkler, Florian Haupt, Martin Heigermoser, Jose Zapardiel-Gonzalo, Jasmin Ohli, Theresa Faure, Evdokia Kalideri, Angela Hommel, Petrina Delivani, Reinhard Berner, Olga Kordonouri, Frank Roloff, Thekla von dem Berge, Karin Lange, Mariusz Oltarzewski, Ryszard Glab, Agnieszka Szypowska, Manu Vatish, John A. Todd, Helena E. Larsson, Anita Ramelius, Jeanette A. Kordel, Kristina Casteels, Jasmin Paulus, Anette G. Ziegler, Ezio Bonifacio, Melanie Guendert, Stefanie Arnolds, Robin Assfalg, Corinna Barz, Karina Blasius, Cigdem Gezginci, Cordula Falk, Joerg Hasford, Bianca Hoefelschweiger, Verena Hoffmann, Manja Jolink, Nana Kwarteng, Ramona Lickert, Claudia Matzke, Rebecca Niewoehner, Michaela Ott, Peter Ruile, Marlon Scholz, Katharina Schuette-Borkovec, Mira Taulien, Lorena Wendel, Katharina Wystub-Lis, Jose Maria Zapardiel Gonzalo, Goele Smeets, Hilde Morobe, Renka Van Heyste, Sophie Achten, Emma Lariviere, Janne Houben, Lionel Marcelis, Uta Ceglarek, Sevina Dietz, Yannick Fuchs, Gita Gemulla, Manja Gottschalk, Sophie Heinke, Anne Karasinsky, Susann Kowal, Fabian Lander, Robert Morgenstern, Katharine Nitzsche, Bianca Schlee, Marina Stopsack, Marc Weigelt, Pauline Wimberger, Marie-Luise Zielmann, Nicole Zubizarreta, Torben Biester, Thomas Danne, Nils Janzen, Ute Holtkamp, Erika Marquardt, Kerstin Semler, Peter Achenbach, Melanie Bunk, Anita Gavrisan, Katharina Gestrich, Willi Graetz, Pascale Heim-Ohmayer, Melanie Herbst, Julia Hirte, Anna Hofelich, Cornelia Kraus, Yvonne Kriesen, Claudia Ramminger, Jennifer Schairer, Susanne Wittich, Stephanie Zillmer, Sylwia Dybkowska, Katarzyna Dzygalo, Lidia Groele, Karolina Dluzniak-Golaska, Dorota Owczarek, Katarzyna Popko, Agnieszka Skrobot, Anna Taczanowska, Beata Zdunczyk, Helena Elding Larsson, Markus Lundgren, Ake Lernmark, Daniel Agardh, Jeanette Akerstrom Kordel, Carin Andren Aronsson, Rasmus Bennet, Charlotte Brundin, Annika Fors, Lina Fransson, Berglind Jonsdottir, Ida Jonsson, Zeliha Mestan, Evelyn Tekum Amboh, Carina Torn, Matthew D Snape, Owen Bendor-Samuel, James Bland, Edward Choi, Rachel Craik, Kimberly Davis, Arancha de la Horra, Yama Farooq, Clare Scudder, Ian Humphrey-Smith, Louise Willis, Tabitha Wishlade" "Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D." "Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization" "Chantal Mathieu" "Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk." "The emotional well-being of parents with children at genetic risk for type 1 diabetes before and during participation in the POInT-study" "Kristina Casteels" "INTRODUCTION: This study examined the emotional impact that parents experience when confronted with an increased genetic risk of type 1 diabetes (T1D) in their child. Population-based screening of neonates for genetic risk of chronic disease carries the risk of increased emotional burden for parents. METHODS: Information was collected using a well-being questionnaire for parents of infants identified as having an increased risk for T1D in a multinational research study. Parents were asked to complete this questionnaire after they were told their child had an increased risk for T1D (Freder1k-study) and at several time points during an intervention study (POInT-study), where oral insulin was administered daily. RESULTS: Data were collected from 2595 parents of 1371 children across five countries. Panic-related anxiety symptoms were reported by only 4.9% after hearing about their child having an increased risk. Symptoms of depression were limited to 19.4% of the parents at the result-communication visit and declined over time during the intervention study. When thinking about their child's risk for developing T1D (disease-specific anxiety), 47.2% worried, felt nervous and tense. Mothers and parents with a first-degree relative (FDR) with T1D reported more symptoms of depression and disease-specific anxiety (p " "In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions" "Eric Mbunwe, P. Van Crombrugge, L. Crenier, M. Coeckelberghs, N. Seret, Katelijn Decochez, Evy Vandemeulebroucke, Christiaan Van Schravendijk, J. Wenzlau" "AIMS/HYPOTHESIS:Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia.METHODS:A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 year.RESULTS:Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk.CONCLUSIONS/INTERPRETATION:These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials." "Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers" "Suna Onengut-Gumuscu, Wei-Min Chen, Oliver Burren, Nick J Cooper, Aaron R Quinlan, Josyf C Mychaleckyj, Emily Farber, Jessica K Bonnie, Michal Szpak, Ellen Schofield, Premanand Achuthan, Hui Guo, Mary D Fortune, Helen Stevens, Neil M Walker, Lucas D Ward, Anshul Kundaje, Manolis Kellis, Mark J Daly, Jeffrey C Barrett, Jason D Cooper, Panos Deloukas, John A. Todd, Chris Wallace, Patrick Concannon, Stephen S Rich, Bart Van der Auwera" "Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal." "Association of IL2RA/CD25 with type 1 diabetes in the Belgian population." "Folefac Aminkeng, Jan Van Autreve, Bobby Koeleman, Christiaan Van Schravendijk" "Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associated with type 1 diabetes (X(2) = 26.8, p" "Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population" "Folefac Aminkeng, Jan Van Autreve, Bobby P C Koeleman, Chris van Schravendijk" "Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associated with type 1 diabetes (χ(2) = 26.8, p < 0.001 for alleles and χ(2) = 29.6, p < 0.001 for genotypes). The C allele (odds ratios [OR] = 1.59) and C/C genotype (OR = 1.56) were identified as susceptibility variants, whereas the A allele (OR = 0.63), A/A genotype (OR = 0.14), and A/C genotype (OR = 0.69) as protective variants. IL-2RA/CD25 is associated with both early-onset and late-onset type 1 diabetes, but with a larger effect size in early-onset disease. There was a nonsignificant tendency toward transmission distortion (p = 0.063). Except a tendency toward younger age at onset in carriers of the C/C genotype, no correlations with disease phenotype, immune markers, HLA-DQ, INS and PTPN22 were observed. Also, the frequency of the susceptible genotype was higher in early-onset compared with late-onset TID patients (p = 0.015). In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers." "Accelerated progression to Type 1 diabetes in the presence of HLA-A*24 and -B*18 is restricted to multiple-islet autoantibody-positive individuals with distinct HLA-DQ- and autoantibody risk profiles" "Else Balke, Eric V Balti, Bart Van der Auwera, Ilse Weets, Olivier Costa, Simke Demeester, Kristina Casteels, Marina Coeckelberghs, Sylvie Tenoutasse, Bart Keymeulen, Danny Pipeleers, Frans Gorus" "OBJECTIVE: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A ∗24, -B ∗18, and -B ∗39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS: Unlike HLA-B ∗18 or -B ∗39, HLA-A ∗24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurredindependently from olderage(P" "Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes" "Jeffrey C Barrett, David G Clayton, Patrick Concannon, Beena Akolkar, Jason D Cooper, Henry A Erlich, Cécile Julier, Grant Morahan, Jørn Nerup, Concepcion Nierras, Vincent Plagnol, Flemming Pociot, Helen Schuilenburg, Deborah J Smyth, Helen Stevens, John A. Todd, Neil M Walker, Stephen S Rich, Bart Van der Auwera" "Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10(-6)). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10(-8)) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27."