Title: Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes
Abstract: Pediatric DiabetesAccepted Articles ORIGINAL ARTICLE Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes Jorma Ilonen, Corresponding Author Jorma Ilonen [email protected] orcid.org/0000-0002-9973-2062 Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland Correspondence Jorma Ilonen, Immunogenetics Laboratory, University of Turku, FI-20014 Turku, Finland. Email: [email protected] for more papers by this authorAntti-Pekka Laine, Antti-Pekka Laine Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, FinlandSearch for more papers by this authorMinna Kiviniemi, Minna Kiviniemi Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, FinlandSearch for more papers by this authorTaina Härkönen, Taina Härkönen Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FinlandSearch for more papers by this authorJohanna Lempainen, Johanna Lempainen Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland Department of Pediatrics, Turku University Hospital, Turku, Finland Department of Clinical Microbiology, Turku University Hospital, Turku, FinlandSearch for more papers by this authorMikael Knip, Mikael Knip orcid.org/0000-0003-0474-0033 Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland Tampere Center for Child Health Research, Tampere University Hospital, Tampere, FinlandSearch for more papers by this authorthe Finnish Pediatric Diabetes Register, Finnish Pediatric Diabetes RegisterSearch for more papers by this author Jorma Ilonen, Corresponding Author Jorma Ilonen [email protected] orcid.org/0000-0002-9973-2062 Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland Correspondence Jorma Ilonen, Immunogenetics Laboratory, University of Turku, FI-20014 Turku, Finland. Email: [email protected] for more papers by this authorAntti-Pekka Laine, Antti-Pekka Laine Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, FinlandSearch for more papers by this authorMinna Kiviniemi, Minna Kiviniemi Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, FinlandSearch for more papers by this authorTaina Härkönen, Taina Härkönen Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FinlandSearch for more papers by this authorJohanna Lempainen, Johanna Lempainen Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland Department of Pediatrics, Turku University Hospital, Turku, Finland Department of Clinical Microbiology, Turku University Hospital, Turku, FinlandSearch for more papers by this authorMikael Knip, Mikael Knip orcid.org/0000-0003-0474-0033 Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland Tampere Center for Child Health Research, Tampere University Hospital, Tampere, FinlandSearch for more papers by this authorthe Finnish Pediatric Diabetes Register, Finnish Pediatric Diabetes RegisterSearch for more papers by this author First published: 10 April 2022 https://doi.org/10.1111/pedi.13340 † A complete list of the investigators of the Finnish Pediatric Diabetes Register can be found in the Appendix This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/pedi.13340. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract We aimed to further characterize demography and genetic associations of type 1 diabetes "endotypes" defined by the first appearing islet specific autoantibodies. We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity. This article is protected by copyright. All rights reserved. Supporting Information Filename Description pedi13340-sup-0001-TableS1.docxWord 2007 document , 16.3 KB Table S1 Comparison of children diagnosed with T1D who had autoantibody patterns suggesting that some of present autoantibodies was also the first appearing and those children where this deduction could not be done. Continuous data (age) are expressed as median (quartiles Q1-Q3) and the differences between groups were assessed using Wilcoxon rank-sum test. Categorical data are expressed as number (%) and were assessed using the Chi square test. pedi13340-sup-0002-TableS2.docxWord 2007 document , 20.3 KB Table S2 HLA DR-DQ haplotype distributions in children diagnosed with T1D. Comparisons of children whose first autoantibody could not be deduced based on autoantibody pattern at diagnosis and those with deducible patterns as well as comparison between groups with GADA and IAA as the deduced first autoantibody. P values from Chi-square test corrected using the FDR method. DR alleles in parentheses show alleles not tested but concluded based on strong allelic association. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Accepted ArticlesAccepted, unedited articles published online and citable. 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