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

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p><em>Context:</em> 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.</p><p><em>Objective:</em> To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR.</p><p><em>Design, Setting, Participants:</em> 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.</p><p><em>Main Outcome Measure:</em> The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR.</p><p><em>Results:</em> A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (<em>P</em> < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (<em>P</em> < 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 (<em>P</em> < 0.0001 and P = 0.0013, respectively).</p><p><em>Conclusions:</em> 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.</p></div>