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Diabetes. 2019 Oct 7. pii: db190329. doi: 10.2337/db19-0329. [Epub ahead of print]

Longitudinal Pattern of First-Phase Insulin Response Is Associated with Genetic Variants Outside the Class II HLA Region in Children with Multiple Autoantibodies.

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Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland,
Medicity, University of Turku, Turku, Finland.
Immunogenetics Laboratory, Institute of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland.
Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
Department of Biostatistics, University of Turku, Turku, Finland.
Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
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.
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.


A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39, and eight SNPs outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change of FPIR over time was significantly different between children with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932) and IKZF4 (rs1701704), genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared to children without susceptibility alleles. The presence of the HLA class I A*24 allele was also associated with steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside class II HLA region may have a significant impact on the longitudinal pattern of FPIR.


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