Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies
- 7 October 2019
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (1), 12-19
- https://doi.org/10.2337/db19-0329
Abstract
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 single nucleotide polymorphisms 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 in FPIR over time was significantly different between those 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 with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.Keywords
Funding Information
- JDRF
- Special Research Funds for Turku, Oulu and Tampere University Hospitals in Finland
- Academy of Finland
- Turku University Foundation
- University of Turku Graduate School Doctoral Programme
- Diabetes Research Foundation in Finland
- Sigrid Juselius Foundation
- Paivikki and Sakari Sohlberg Foundation
- Emil Aaltonen Foundation
- Alma and KA Snellman Foundation
- Kyllikki and Uolevi Lehikoinen Foundation
- Turku Centre of Lifespan Research
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