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Objectives: We aimed to further characterize demography and genetic associations of type 1 diabetes “endotypes” defined by the first appearing islet specific autoantibodies. Research Design and Methods: We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results: Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions: The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity. publishedVersion

AIM: We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during fall and winter, the colder seasons with consistently observed higher incidence of type 1 diabetes. METHODS: Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents. Metabolic characteristics, beta-cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis. RESULTS: Significant seasonality was observed with higher number of new cases during fall and winter (n = 1353/27.1% and n = 1286/25.8%) compared with spring and summer (n = 1135/22.7% and n = 219/24.4%) (p

Aim: To determine the association of HLA class II risk with the demographic and clinical characteristics of type 1 diabetes at diagnosis. Methods: We conducted a register-based retrospective cohort study of 4993 Finnish children (2169 girls) – diagnosed with type 1 diabetes under the age of 15 years in 2003–2016. The participants were divided into six risk groups based on their HLA DR/DQ genotype. Demographic characteristics, family history of type 1 diabetes and metabolic markers at the time of diagnosis were compared between the groups. Results: In total, 4056/4993 children (81.2%) carried an HLA genotype associated with an increased risk of type 1 diabetes (risk groups 3–5), whereas 937/4993 children (18.8%) carried a HLA genotype conferring no or decreased disease risk. Children with higher HLA risk were younger at diagnosis (p < 0.001) and had a shorter duration of classical symptoms before diagnosis (p = 0.016). Subjects in the high-risk group were more likely to have a family member affected by type 1 diabetes when compared to those in the neutral risk group (11.5% vs. 8.8%, p = 0.05). Conclusion: Children with stronger HLA disease susceptibility are younger at their disease manifestation and have a shorter period of symptoms before diagnosis, suggesting that the HLA class II genes are associated with a more aggressive disease presentation. publishedVersion

AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity.MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers.ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations.ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored.Trial registry numberNCT00179777

Aims/hypothesis Shared aetiopathogenetic factors have been proposed in type 1 diabetes and type 2 diabetes and both diseases have been shown to cluster in families. Characteristics related to type 2 diabetes have been described in patients with type 1 diabetes with a positive family history of type 2 diabetes. We wanted to characterise the family history of type 2 diabetes and its possible effects on the phenotype and genotype of type 1 diabetes in affected children at diagnosis. Methods A total of 4993 children under the age of 15 years with newly diagnosed type 1 diabetes from the Finnish Pediatric Diabetes Register were recruited (56.6% boys, median age of 8.2 years) for a cross-sectional, observational, population-based investigation. The family history of diabetes at diagnosis was determined by a structured questionnaire, and markers of metabolic derangement, autoantibodies and HLA class II genetics at diagnosis were analysed. Results Two per cent of the children had an immediate family member and 36% had grandparents with type 2 diabetes. Fathers and grandfathers were affected by type 2 diabetes more often than mothers and grandmothers. The children with a positive family history for type 2 diabetes were older at the diagnosis of type 1 diabetes (p p = 0.01) and more often tested negative for all diabetes-related autoantibodies (p = 0.02). Conclusions/interpretation Features associated with type 2 diabetes, such as higher body weight, older age at diagnosis and autoantibody negativity, are more frequently already present at the diagnosis of type 1 diabetes in children with a positive family history of type 2 diabetes. Graphical abstract

Background Circulating fatty acids have been linked to development of type 1 diabetes. Objectives To study the prospective associations of serum fatty acids with the risk of islet autoimmunity in high-risk children. Methods A nested case-control selection was carried out within the TRIGR cohort, which included infants with HLA (DQB1 or DQA1)-conferred disease susceptibility and a first-degree relative with type 1 diabetes, born between 2002 and 2007 in 15 countries and followed-up until 2017. The present study included 244 case children positive for at least two islet autoantibodies (ICA, IAA, GADA, and IA-2A) and two control children were matched for country and age. Proportions of 26 serum fatty acids at cord blood and at 6, 12, and 18 months of age were assessed using gas-chromatography. Results The average proportions of the following fatty acids were associated with an increased risk of islet autoimmunity, adjusted for sex, HLA risk, and maternal type 1 diabetes: pentadecanoic acid (15:0) (OR 3.41: 95% CI 1.70, 6.85), heptadecanoic acid (iso 17:0) (2.64: 1.62, 4.28) and (anteiso 17:0) (2.27: 1.39, 3.70), stearic acid (18:0) (23.8: 2.32, 244.6), and conjugated linoleic acid (18:2n-7) (2.60: 1.47, 4.59). Breastfeeding and not having maternal type 1 diabetes were positively associated with levels of the above-mentioned fatty acids. N-3 fatty acids were not consistently associated with islet autoimmunity. Conclusions We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes.