Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies - UTU Research Portal

A1 Refereed original research article in a scientific journal

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

Authors: Maarit K. Koskinen, Mari-Liis Mikk, Antti-Pekka Laine, Johanna Lempainen, Eliisa Löyttyniemi, Paula Vähäsalo, Anne Hekkala, Taina Härkönen, Minna Kiviniemi, Olli Simell, Mikael Knip, Riitta Veijola, Jorma Ilonen, Jorma Toppari

Publisher: American Diabetes Association

Publication year: 2020

Journal: Diabetes

Journal name in source: Diabetes

Journal acronym: Diabetes

Volume: 69

Issue: 1

First page : 12

Last page: 19

Number of pages: 8

ISSN: 0012-1797

eISSN: 1939-327X

DOI: https://doi.org/10.2337/db19-0329(external)

Web address : https://diabetesjournals.org/diabetes/article/69/1/12/39619/Longitudinal-Pattern-of-First-Phase-Insulin(external)

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.