Sex, family history, and seasonal variation in relation to the phenotype and genotype at diagnosis of type 1 diabetes

Type 1 diabetes (T1D) is an immune-mediated disorder characterized by autoimmunity to pancreatic beta cells and progressively leading to acute onset of hyperglycemia and dependence on exogenous insulin. Finland has the highest incidence of T1D worldwide. In high-incidence countries, the disease affects more males than females. The risk of developing T1D can be assessed based on human leucocyte antigen (HLA) genotypes alone or in combination with non-HLA genetic polymorphisms and by following the development of diabetes-associated autoantibodies. The disease risk is higher in the family members of patients with T1D compared to the general population. The etiology of T1D is believed to be multifactorial and involves both genetic and environmental factors. Moreover, there is heterogeneity in the disease pathogenesis and progression, and this might be associated with the variability in the phenotype and genotype of T1D at clinical disease presentation. This thesis aimed to describe disease severity at diagnosis of T1D characterized by metabolic, immunological and genetic factors associated with sex, family history of diabetes and seasonal timing of the disease manifestation. The study subjects in this thesis are participants in the Finnish Pediatric Diabetes Register and Sample Repository. HLA genetics and diabetes-related autoantibodies were analyzed soon after the diagnosis of T1D. A structured questionnaire is used for collecting information on the metabolic decompensation at diagnosis and on the family history of any type of diabetes in first-degree relatives (FDR) and grandparents. This thesis assessed the characteristics at diagnosis in 4993 Finnish children and adolescents newly diagnosed with T1D between 2003 and 2016. Family history of T1D was reported in 10.4% of all children, and fathers were more commonly affected than mothers or siblings (5.1% vs. 2.8% vs. 1.9%). The presence of paternal T1D was associated with a more severe disease phenotype at diagnosis of T1D compared to a history of maternal T1D, which has not been reported earlier. A male preponderance was observed among the parents diagnosed before the birth of the index child, while the male-female ratio was similar in the parents diagnosed after the birth of the index child, which support the idea of a protective effect of maternal type 1 diabetes via insulin treatment during pregnancy. Genetic factors may also partly explain the phenomenon, as the high-risk HLA haplotype DR4-DQ8 was more prevalent in familial vs. sporadic cases and especially in children with an affected father. Two percent of the index children reported type 2 diabetes (T2D) in their FDRs, the corresponding proportion for grandparents being 36%. Fathers and grandfathers were more commonly affected with T2D than mothers and grandmothers. Family history of T2D seemed to present with a mixed phenotype of both major types of diabetes associated features, as it was associated with older age at diagnosis, higher BMI z-score and more frequent autoantibody negativity. Girls seemed to have poorer glycemic control and signs of a more severe metabolic derangement at the diagnosis of the disease. Boys, however, more often tested positive for three of four biochemical autoantibodies (IAA, IA-2A, and ZnT8A) while only GADA positivity was more common in girls. Significant seasonality in T1D onset was observed with higher frequency of new diagnoses in fall and winter. The youngest children (aged 0.5–4 years), however, differed from older children as the minority of them were diagnosed in winter, suggesting that different environmental factors may play a key role at different ages. Poorer metabolic decompensation was associated with seasons with the lowest number of diagnoses and is more likely to be explained by a delay in seeking medical help or the reduced medical services during summer holidays than by a more aggressive autoimmunity. This thesis provides updated information on the prevalence of T1D and T2D among the family members of newly diagnosed Finnish children with T1D. The observed frequencies are in line with previous reports. In addition, this thesis improves the identification of patients with the highest risk of an aggressive disease process at the diagnosis of T1D. The disease features at the time of diagnosis may also predict later glycemic control and risk of long-term complications. The early recognition of factors related to a more adverse disease course may help us to create future strategies for disease management and prevent later disease-related complications. Future studies with prospective follow-up after the diagnosis are required to confirm these assumptions. Furthermore, our results emphasize heterogeneity in the disease etiology and pathogenesis. In the future, a more accurate diagnosis and individualized treatment methods should be used in the care of children and adolescents affected by T1D.