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Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood

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Title: Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood
Authors: Jorma Ilonen, Witold Bauer, Jorma Toppari, Minna Kiviniemi, Taina Härkönen, Johanna Lempainen, Attila Gyenesei, Mikael Knip, Riitta Veijola
Contributors: Diabetes and Obesity Research Program, Staff Services, HUS Children and Adolescents, Research Programs Unit, Children's Hospital, University of Helsinki, Research Group Knip
Source: The Journal of Clinical Endocrinology & Metabolism. 104:4521-4530
Publisher Information: The Endocrine Society, 2019.
Publication Year: 2019
Subject Terms: Male, 0301 basic medicine, GENETIC SUSCEPTIBILITY, Insulin Antibodies, CHILDREN, Autoimmunity, Kaplan-Meier Estimate, APPEARANCE, Cohort Studies, HLA-DQ antigens - genetics, Diabetes mellitus, 0302 clinical medicine, Longitudinal Studies, Child, 10. No inequality, RISK, Glutamate Decarboxylase, Longitudinal studies, Age Factors, type 1 - genetics, INSULIN, General medicine, internal medicine and other clinical medicine, 3. Good health, POSITIVITY, Seroconversion, Child, Preschool, type 1 - immunology, Disease Progression, Cohort studies, Female, Age factors, Glutamate decarboxylase - immunology, Insulin antibodies - immunology, Proportional hazards models, Adolescent, Genotype, Kaplan-Meier estimate, RELATIVES, Genetic predisposition to disease, PHENOTYPES, ta3111, Autoantibodies - immunology, preschool, 03 medical and health sciences, HLA-DQ Antigens, Humans, Genetic Predisposition to Disease, TYPE-1, Autoantibodies, Autoimmunity - immunology, Disease progression, Infant, HLA-DR Antigens, ALLELES, Biomedicine, Diabetes Mellitus, Type 1, HLA-DR antigens - genetics
Description: Context Children with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process. Objective To compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody. Design and methods A cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses. Results Persistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody. Conclusions Findings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
Document Type: Article
File Description: application/pdf
Language: English
ISSN: 1945-7197
0021-972X
DOI: 10.1210/jc.2019-00421
DOI: 10.1210/jc.201900421
Access URL: https://academic.oup.com/jcem/article-pdf/104/10/4521/29224184/jc.2019-00421.pdf
https://pubmed.ncbi.nlm.nih.gov/31120497
http://juuli.fi/Record/0361900119
https://doi.org/10.1210/jc.201900421
https://www.ncbi.nlm.nih.gov/pubmed/31120497
https://researchportal.helsinki.fi/en/publications/age-at-seroconversion-hla-genotype-and-specificity-of-autoantibod
https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2019-00421/5497099
https://academic.oup.com/jcem/article/104/10/4521/5497099
https://academic.oup.com/jcem/article/104/10/4521/5497099
https://doi.org/10.1210/jc.2019-00421
http://hdl.handle.net/10138/312969
Accession Number: edsair.doi.dedup.....286b5523a64545c8fa9f27bcc9a18371
Database: OpenAIRE
Description
Abstract:Context Children with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process. Objective To compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody. Design and methods A cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses. Results Persistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody. Conclusions Findings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
ISSN:19457197
0021972X
DOI:10.1210/jc.2019-00421