Family history of type 2 diabetes delays development of type 1 diabetes in TEDDY children with islet autoimmunity

Abstract

<h3>Aims/hypothesis</h3><p>The aetiology of type 1 diabetes remains elusive. Family history of type 1 diabetes increases the disease risk but the role of other autoimmune diseases or type 2 diabetes in the family are unclear. Here, we aimed to analyse the effect of family history of diabetes and autoimmune diseases on development of islet autoimmunity and progression to type 1 diabetes.</p><h3>Methods</h3><p>The Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective observational cohort study of children recruited as newborns in 2004–2010 at clinical centres in Finland, Germany, Sweden and the USA. A total of 8676 children with high-risk <em>HLA-DR-DQ</em> genotype for type 1 diabetes fulfilled the eligibility criteria for regular follow-up. Questionnaire-based family history of all types of diabetes and autoimmune diseases among first- and second-degree relatives (FDRs and SDRs; data available for 8558 and 7479 children, respectively) was collected. The main outcomes were development of islet autoimmunity and progression from autoimmunity to type 1 diabetes. Data until 31 January 2016 were analysed.</p><h3>Results</h3><p>Persistent islet autoantibodies were found in 669 children and type 1 diabetes in 233 children (45% and 46% female sex, respectively). The median follow-up time after seroconversion was 6.5 years (IQR 3.3–8.5). Having an FDR with type 1 diabetes increased the child’s risk of islet autoimmunity (HR 2.2 [95% CI 1.8, 2.8]; <em>p</em><0.001), particularly if the father or sibling had type 1 diabetes. Islet autoimmunity was also associated with family history of type 1 diabetes in an SDR when participants having an FDR with type 1 diabetes were excluded from the analysis (HR 1.4 [95% CI 1.1, 1.8]; <em>p</em>=0.017). Notably, progression from autoantibody positivity to type 1 diabetes was significantly delayed in children having type 2 diabetes in an SDR (HR 0.61 [95% CI 0.44, 0.86]; <em>p</em>=0.004). Islet autoimmunity or progression to type 1 diabetes were not associated with other types of diabetes or autoimmune diseases in the family.</p><h3>Conclusions/interpretation</h3><p>Family history of diabetes is differentially associated with development of islet autoimmunity and progression to type 1 diabetes. The contribution made by familial, genetic and environmental factors to the two phases of the disease pathogenesis deserves distinct analyses.</p>