Coxsackievirus B Infections Are Associated With the Risk of Islet Autoimmunity in Children With Strong Genetic Susceptibility to Type 1 Diabetes: Results From the TRIGR Divia Study

Abstract

Aims: Especially, the coxsackievirus B group of enteroviruses has been linked to the development of islet autoimmunity and type 1 diabetes in genetically susceptible individuals. Our aim was to study the possible associations of 10 different microbial infections with islet autoimmunity in a large international prospective study. Materials and Methods: In a nested case-control study within the TRIGR study, follow-up serum samples from 240 islet autoantibody-positive case children and 436 age- and country-matched control children were analysed for IgG class antibodies against 10 different respiratory and gastrointestinal microbes using an enzyme immunoassay, and for neutralising antibodies against all six coxsackievirus B types. The samples were obtained at several time points prior to and at the time of seroconversion for multiple islet autoantibodies. All children had a first-degree relative with type 1 diabetes, and they carried risk-associated HLA-DQ alleles. Results: Coxsackievirus B5 was associated with an increased risk of islet autoimmunity (OR 2.22, 95% CI 1.29–3.80, p = 0.004, corrected p = 0.024), which remained after adjustment for HLA, sex, and maternal type 1 diabetes. This association was particularly seen for infections occurring more than 12 months (OR 2.02, 95% CI 1.06–3.84, p = 0.032) and 0–6 months (OR 2.66, 95% CI 1.11–6.35, p = 0.028) before the first detection of multiple islet autoantibodies. After correction for multiple comparisons, none of the other viruses showed an association with islet autoimmunity. Conclusions: This study supports previous evidence of the risk association of coxsackievirus B infections. These results support the role of certain virus infections as possible modulating factors in the pathogenesis of type 1 diabetes.