University of Oulu

Koskinen, M. K., Lempainen, J., Löyttyniemi, E., Helminen, O., Hekkala, A., Härkönen, T., … Veijola, R. (2017). Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies. The Journal of Clinical Endocrinology & Metabolism, 103(8), 2870–2878.

Class II HLA genotype association with first-phase insulin response is explained by islet autoantibodies

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Author: Koskinen, Maarit K.1; Lempainen, Johanna1,2; Löyttyniemi, Eliisa3;
Organizations: 1Department of Pediatrics, University of Turku and Turku University Hospital, FI-20520 Turku, Finland
2Immunogenetics Laboratory, Institute of Biomedicine, University of Turku and Turku University Hospital, FI-20520 Turku, Finland
3Department of Biostatistics, University of Turku, FI-20520 Turku, Finland
4Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, FI-90014 Oulu, Finland
5Children ’ s Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland
6Research Programs Unit, Diabetes and Obesity, University of Helsinki, FI-00290 Helsinki, Finland
7Folkhälsan Research Center, FI-00290 Helsinki, Finland
8Tampere Center for Child Health Research, Tampere University Hospital, FI-33014 Tampere, Finland
9Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, FI-20520 Turku, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
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Language: English
Published: Endocrine society, 2018
Publish Date: 2019-09-20


Context: A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both.

Objective: To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR.

Design, Setting, Participants: A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR.

Main Outcome Measure: The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR.

Results: A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively).

Conclusions: The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

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Series: Journal of clinical endocrinology & metabolism
ISSN: 0021-972X
ISSN-E: 1945-7197
ISSN-L: 0021-972X
Volume: 103
Issue: 8
Pages: 2870 - 2878
DOI: 10.1210/jc.2017-02040
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: This study was funded by the Juvenile Diabetes Research Foundation; the European Union; the Novo Nordisk Foundation, the Special Research Funds for Turku, Oulu, and Tampere University Hospitals in Finland; the Academy of Finland; the National Technology Agency of Finland; Finnish Office for Health Technology Assessment; the Turku University Foundation; the University of Turku Graduate School Doctoral Programme; the Diabetes Research Foundation in Finland; the Sigrid Juselius Foundation; the Päivikki and Sakari Sohlberg Foundation; the Emil Aaltonen Foundation; the Jalmari and Rauha Ahokas Foundation; the Signe and Ane Gyllenberg Foundation; the Research Foundation of Orion Corporation; the Foundation for Pediatric Research; and the Alma and KA Snellman Foundation.
Copyright information: © 2018 Endocrine Society. This article has been published under the terms of the Creative Commons Attribution License (CC BY;