A quarter of patients with type 1 diabetes have co‐existing non‐islet autoimmunity: the findings of a UK population‐based family study

Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+/K+‐ATPase (ATPA) and their genetic associations in a well‐characterized population‐based cohort of individuals with T1D from the Bart's–Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR‐SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti‐glutamate decarboxylase autoantibodies were predictive of co‐existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3‐DQ2, with the DR3‐DQ2/DR3‐DQ2 genotype conferring the highest risk, followed by DR4‐DQ8/DR4‐DQ8. ATPA were associated with DR3‐DQ2, DRB1*0404 (in males) and the DR3‐DQ2/DR4‐DQ8 genotype. TPOA were associated with the DR3‐DQ2/DR3‐DQ2 genotype. Almost one‐quarter of patients diagnosed with T1D aged under 21 years have at least one other organ‐specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.

[1]  R. B. Farnsworth.  Pernicious Anemia , 2020, Definitions.

[2]  J. Wenzlau,et al.  Luminescent Immunoprecipitation System (LIPS) for Detection of Autoantibodies Against ATP4A and ATP4B Subunits of Gastric Proton Pump H+,K+-ATPase in Atrophic Body Gastritis Patients , 2017, Clinical and translational gastroenterology.

[3]  M. Bălgrădean,et al.  Type 1 Diabetes and Thyroid Autoimmunity in Children. , 2016, Maedica.

[4]  T. Gardner,et al.  ATPase4A Autoreactivity and Its Association With Autoimmune Phenotypes in the Type 1 Diabetes Genetics Consortium Study , 2015, Diabetes Care.

[5]  Å. Lernmark,et al.  Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association , 2015, Diabetes Care.

[6]  J. Ludvigsson,et al.  Systematic review with meta‐analysis: associations between coeliac disease and type 1 diabetes , 2014, Alimentary pharmacology & therapeutics.

[7]  P. Bingley,et al.  Risk of pediatric celiac disease according to HLA haplotype and country , 2014, Indian Pediatrics.

[8]  J. Ilonen,et al.  Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. , 2014, JAMA.

[9]  Mohammad Sohel Rahman,et al.  A Study of Autoimmune Polyglandular Syndrome (APS) in Patients with Type1 Diabetes Mellitus (T1DM) Followed Up at a Teritiary Care Hospital. , 2014, Journal of clinical and diagnostic research : JCDR.

[10]  S. Twigg,et al.  Thyroid autoimmunity in Type 1 diabetes: systematic review and meta‐analysis , 2014, Diabetic medicine : a journal of the British Diabetic Association.

[11]  E. Louis,et al.  [The thyrogastric syndrome: its effects on micronutriments and gastric tumorigenesis]. , 2013, Revue medicale de Liege.

[12]  G. Zuccotti,et al.  Type 1 diabetes and celiac disease: The effects of gluten free diet on metabolic control. , 2013, World journal of diabetes.

[13]  P. Bingley,et al.  Rising Incidence of Type 1 Diabetes Is Associated With Altered Immunophenotype at Diagnosis , 2012, Diabetes.

[14]  T. Gardner,et al.  Development of a novel autoantibody assay for autoimmune gastritis in type 1 diabetic individuals , 2011, Diabetes/metabolism research and reviews.

[15]  Y. Yamaoka,et al.  Epidemiology of Helicobacter pylori Infection and Public Health Implications , 2011, Helicobacter.

[16]  M. Rewers,et al.  Additional Autoimmune Disease Found in 33% of Patients at Type 1 Diabetes Onset , 2011, Diabetes Care.

[17]  E. Critselis,et al.  The prevalence and risk factors for coeliac disease among children and adolescents with type 1 diabetes mellitus. , 2010, Diabetes research and clinical practice.

[18]  T. Battelino,et al.  An influence of HLA-A, B, DR, DQ, and MICA on the occurrence of Celiac disease in patients with type 1 diabetes. , 2010, Tissue antigens.

[19]  John A Todd,et al.  Etiology of type 1 diabetes. , 2010, Immunity.

[20]  E. Bouajina,et al.  Type 1 diabetes mellitus, celiac disease, systemic lupus erythematosus and systemic scleroderma in a 15-year-old girl , 2010, Rheumatology International.

[21]  K. Karavanaki,et al.  Factors for thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus , 2009, Upsala journal of medical sciences.

[22]  E. Bergseng,et al.  Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation , 2009, Nature Immunology.

[23]  Y. Shoenfeld,et al.  Anti‐infectious Antibodies and Autoimmune‐associated Autoantibodies in Patients with Type I Diabetes Mellitus and their Close Family Members , 2009, Annals of the New York Academy of Sciences.

[24]  K. Karavanaki,et al.  Screening for Associated Autoimmunity in Children and Adolescents with Type 1 Diabetes Mellitus (T1DM) , 2009, Hormone Research in Paediatrics.

[25]  Ying-Chu Lee,et al.  Regulation of beta cell replication , 2009, Molecular and Cellular Endocrinology.

[26]  O. Kordonouri,et al.  Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus – data from a German/Austrian multicentre survey , 2008, Pediatric diabetes.

[27]  W. Shreffler,et al.  Type 1 diabetes, autoimmune thyroid disease, and chronic urticaria , 2008, Pediatric diabetes.

[28]  R. Guimarães,et al.  Prevalence of autoimmune thyroid disease and thyroid dysfunction in young Brazilian patients with type 1 diabetes , 2008, Pediatric diabetes.

[29]  Å. Lernmark,et al.  Annual screening detects celiac disease in children with type 1 diabetes , 2008, Pediatric diabetes.

[30]  G. Morahan,et al.  The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes , 2008, Diabetes Care.

[31]  S. Hofer,et al.  Polyendocrinopathy in Children, Adolescents, and Young Adults With Type 1 Diabetes , 2008, Diabetes Care.

[32]  S. Savva,et al.  Rising incidence of type 1 diabetes mellitus in children and adolescents in Cyprus in 2000–2004 , 2007, Pediatric diabetes.

[33]  G. Dahlquist,et al.  Worldwide childhood type 1 diabetes incidence – what can we learn from epidemiology? , 2007, Pediatric diabetes.

[34]  Z. Orbak,et al.  Prevalence of celiac disease in a sample of Turkish children and adolescents with type 1 diabetes mellitus. , 2006, Journal of clinical gastroenterology.

[35]  Y. Tomer,et al.  Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. , 2005, The Journal of clinical endocrinology and metabolism.

[36]  Marian Rewers,et al.  Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? , 2005, Gastroenterology.

[37]  O. Kordonouri,et al.  Anthropometry, metabolic control, and thyroid autoimmunity in type 1 diabetes with celiac disease: A multicenter survey. , 2004, The Journal of pediatrics.

[38]  P. Bingley,et al.  The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes , 2004, The Lancet.

[39]  P. Bingley,et al.  Undiagnosed coeliac disease at age seven: population based prospective birth cohort study , 2004, BMJ : British Medical Journal.

[40]  O. Kordonouri,et al.  Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. , 2002, Diabetes care.

[41]  O. Kordonouri,et al.  Predictivity of thyroid autoantibodies for the development of thyroid disorders in children and adolescents with Type 1 diabetes , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[42]  G. Barera,et al.  Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. , 2002, Pediatrics.

[43]  W Harry Hannon,et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). , 2002, The Journal of clinical endocrinology and metabolism.

[44]  E. van Marck,et al.  Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in type 1 diabetes mellitus , 2002, Alimentary pharmacology & therapeutics.

[45]  J. Vertommen,et al.  Beta‐cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA‐DQ types in type 1 diabetes , 2001, Clinical and experimental immunology.

[46]  P. Bingley,et al.  HLA class II typing of whole genome amplified mouth swab DNA. , 2000, Tissue antigens.

[47]  J. Tuomilehto,et al.  Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends , 1999, Diabetologia.

[48]  R. Holl,et al.  Thyroid Autoimmunity in Children and Adolescents with Type 1 Diabetes mellitus , 1999, Hormone Research in Paediatrics.

[49]  M. Rewers,et al.  One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. , 1999, Journal of autoimmunity.

[50]  J. Soler,et al.  Clinical presentation and early course of type 1 diabetes in patients with and without thyroid autoimmunity. , 1999, Diabetes care.

[51]  J. Vertommen,et al.  In New‐onset Insulin‐dependent Diabetic Patients the Presence of Anti‐thyroid Peroxidase Antibodies is Associated with Islet Cell Autoimmunity and the High Risk Haplotype HLA DQA1*0301‐DQB1*0302 , 1996, Diabetic medicine : a journal of the British Diabetic Association.

[52]  S. Nagataki,et al.  Autoantibodies to Glutamic Acid Decarboxylase in Patients with IDDM and Autoimmune Thyroid Disease , 1994, Diabetes.

[53]  R. Carmel.  Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race , 1992, Clinical and experimental immunology.

[54]  S. Ahmed,et al.  Sex hormones and the immune system--Part 2. Animal data. , 1990, Bailliere's clinical rheumatology.

[55]  P. Bingley,et al.  Incidence of insulin dependent diabetes in England: a study in the Oxford region, 1985-6. , 1989, BMJ.

[56]  N. Talal.  Disordered Immunologic Regulation and Autoimmunity , 1976, Birth defects original article series.

[57]  Orbit,et al.  Shared Genetic Basis for Type 1 Diabetes, Islet Autoantibodies, and Autoantibodies Associated With Other Immune-Mediated Diseases in Families With Type 1 Diabetes-DTU Orbit (03/12/2018) , 2018 .

[58]  J. Stockman,et al.  Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study , 2011 .

[59]  L. V. Van Gaal,et al.  Autoimmune gastritis in type 1 diabetes: a clinically oriented review. , 2008, The Journal of clinical endocrinology and metabolism.

[60]  E. van Marck,et al.  Autoimmune gastropathy in type 1 diabetic patients with parietal cell antibodies: histological and clinical findings. , 2003, Diabetes care.

[61]  R. Bretzel,et al.  Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects. , 2001, Diabetes care.

[62]  A. Bredberg,et al.  Serological screening for celiac disease in healthy 2.5-year-old children in Sweden. , 2001, Pediatrics.

[63]  M. Rewers,et al.  Annals of the New York Academy of Sciences Pathogenesis of Type 1 Diabetes: Lessons from Natural History Studies of High-risk Individuals , 2022 .