The phenotype and genotype of children with newly diagnosed type 1 diabetes in relation to family history of type 1 diabetes and other autoimmune diseases

Type 1 diabetes (T1D) is an immune-mediated disease that affects ~0.7% of children in Finland. Its incidence is the highest in Finland worldwide. The proposed etiology of T1D is both genetic and environmental. Many of these etiological factors are shared between other autoimmune diseases (AIDs) and, accordingly, these diseases co-occur in patients with T1D and their relatives. This thesis aims at characterizing the frequency of additional autoimmunity in Finnish children under the age of 15 years with newly diagnosed T1D and in their extended family members, as well as characterizing the effects of this additional autoimmunity on clinical, metabolic, and genetic markers, and T1D autoantibodies. The subjects for this thesis are participants of the Finnish Pediatric Diabetes Register and Sample Repository. Participating families fill in questionnaires on the clinical parameters, family characteristics, and diabetes and other diseases of the index child and family members. This thesis analysed data from the time of diagnosis on 2245 children diagnosed with T1D between 2002 and 2009. The mean age at diagnosis of T1D for the study population was 7.9 years and the majority were boys (57.1%). For a subset of the cases, follow-up data was available. Additional AIDs were reported by 1.6% children at diagnosis and by 3.2% after a median eight years of follow-up. More than 20% of the families reported first- and/or second-degree relatives with T1D, and over a third, relatives with other AIDs. Fathers were more often affected by T1D compared to mothers (6 vs. 3%), whereas mothers were more often affected by other AIDs (10 vs. 4%). Girls had more often T1D affected paternal and boys T1D affected maternal second-degree relatives. Transient anti-tTG not developing to CD seemed more common among children with T1D than among their relatives. The HLA-DR3-DQ2 haplotype was associated with CD autoimmunity and the HLA-DR4-DQ8 haplotype with familial T1D. Also, non-HLA loci were shown to contribute to the clustering of AIDs in children with multiple AIDs and in autoimmune families. Familial T1D, even with only second-degree relatives affected, leads to less severe onset of T1D in the index child. This thesis provides current estimates of the frequency of additional autoimmunity in Finnish children with newly diagnosed T1D and in their relatives. These figures are in line with those reported previously internationally and in Finland. Novel discoveries were the milder clinical onset of T1D in familial T1D even if only second-degree relatives were affected (readily explained by the increased awareness of the disease in these families), and the gender difference of girls having paternal and boys maternal second-degree relatives affected by T1D. This gender difference, transient anti-tTG among children with T1D at diagnosis, and the reported candidate non-HLA SNPs for clustered autoimmunity require validation by further studies.Tyypin 1 diabetes on immuunivälitteinen sairaus, jota sairastaa n. 0,7% suomalaisista lapsista. Suomessa tautiin sairastuvuus on korkeinta koko maailmassa. Tyypin 1 diabeteksen syntymissyyt ajatellaan liittyvän sekä genetiikkaan että ympäristötekijöihin. Monet näistä tekijöistä ovat yhteisiä myös muille autoimmuunisairauksille, kuten esimerkiksi keliakialle ja reumasairauksille. Siksi nämä taudit esiintyvät usein yhdessä. Tässä väitöskirjatutkimuksessa selvitettiin Suomessa vuosina 2002-2009 tyypin 1 diabetekseen sairastuneiden alle 15-vuotiaiden lasten omaa ja perhehistoriaa muiden autoimmuunisairauksien osalta diagnoosihetkellä sekä osittain myös n. 8 vuoden seurannan aikana. Lisäksi vertailtiin diagnoosihetken kliinistä tilannetta, autovasta-aineita sekä genetiikkaa autoimmuunisairauksien esiintymisen suhteen. Mukana työssä oli yhteensä 2245 tyypin 1 diabetekseen sairastunutta lasta valtakunnallisesta lasten diabetesrekisteristä sekä heidän perheenjäsenensä. Tiedot perheen autoimmuunisairauksista saatiin pääasiassa rekisteriin kuuluvalta kyselylomakkeelta, mutta osittain käytettiin myös Kelan rekistereitä ja keliakiaan liittyviä vasta-aineita seulottiin osalta osallistujista. Tutkimuksen lapsista 1,6%:lla oli jokin muu autoimmuunisairaus jo diabeteksen diagnoosihetkellä ja luku nousi yli 3%:iin seurannassa. Joka viidennellä oli sukulaisia, jotka sairastavat tyypin 1 diabetesta ja kolmasosalla sukulaisia, joilla on jokin muu autoimmuunisairaus. Lasten HLA-genetiikassa oli eroa riippuen autoimmuunitaustasta: esimerkiksi tyypin 1 diabeteksen ja keliakian yhdessä esiintyminen liittyi HLA-DR3-DQ2 genotyyppiin, kun taas lapsilla, joilla on perheessä tyypin 1 diabetesta, oli useammin HLA-DR4-DQ8 genotyyppi. Muutkin geenialueet kuin HLA vaikuttivat autoimmuunisairauksien esiintymiseen yhdessä. Metabolinen tilanne oli diagnoosihetkellä rauhallisempi, esim. verensokeritasot matalammat, paino ehtinyt laskea vähemmän ja diabeettista ketoasidoosia vähemmän, jos perheessä oli muita tyypin 1 diabetesta sairastavia, vaikka he olisivatkin kaukaisempia sukulaisia (esim. setä, täti, isovanhempi). Vaikka näissä perheissä diabetesoireet tunnistetaan helpommin, potentiaalisesti hengenvaarallista ketoasidoosia esiintyi silti lähes 10%:lla. Parantamisen varaa varhaisessa diagnosoimisessa siis edelleen on. Tutkimuksella saatiin ajankohtaista tietoa diabetesta sairastavien lasten ja heidän perheensä sairastavuudesta muiden autoimmuunisairauksien osalta. Nämä osuudet pitkälti vastaavat kansainvälistä tasoa. Eroavaisuuksia genetiikassa ja kliinisessä tilanteessa oli nähtävissä riippuen autoimmuunitaustasta. Osa tuloksista, kuten esimerkiksi tiettyjen HLA:n ulkopuolisten geenien merkitys, vaativat lisätutkimuksia

Altered temporal connectivity and reduced meta-state dynamism in adolescents born very preterm

Adolescents born very preterm have an increased risk for anxiety, social difficulties and inattentiveness, i.e. the ‘preterm behavioural phenotype’. The extreme end of these traits comprises the core diagnostic features of attention and hyperactivity disorders and autism spectrum disorder, which have been reported to show aberrant dynamic resting-state functional network connectivity. This study aimed to compare this dynamism between adolescents born very preterm and controls. A resting-state functional magnetic resonance imaging was performed on 24 adolescents born very preterm (gestational agePeer reviewe

Seasonality in the manifestation of type 1 diabetes varies according to age at diagnosis in Finnish children

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 < 0.001). The youngest children (aged 0.5-4 years) differed from the older ones (aged 5-14 years) as a minority of them were diagnosed in winter (p = 0.019) while the older children followed the same pattern as that seen in the total series. Poorer metabolic decompensation was observed during seasons with lower number of new diagnoses. Conclusion The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.Peer reviewe

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes

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 <0.001), had higher BMI-for-age (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.Peer reviewe

Seasonality in the manifestation of type 1 diabetes varies according to age at diagnosis in Finnish children

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 Conclusion: The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.</p

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes

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.ResultsTwo 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/interpretationFeatures 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.</p

Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis

Aims/hypothesis In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers.We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives.Methods A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire.Results Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; pConclusions/interpretation The more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.</p

HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first-or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.Peer reviewe

Characteristics of familial type 1 diabetes : effects of the relationship to the affected family member on phenotype and genotype at diagnosis

Aims/hypothesis In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives. Methods A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire. Results Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p <0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p = 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p = 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p = 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p = 0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p = 0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p = 0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p <0.05). When comparing index children with affected parents diagnosed before or after the birth of the index child, a clear male preponderance was seen among the affected parents diagnosed before the birth of the index child (fathers 66.2% vs mothers 33.8%; p = 0.006), whereas the proportion of fathers and mothers was similar if type 1 diabetes was diagnosed after the birth of the index child. Conclusions/interpretation The more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.Peer reviewe

Contrasting microbiotas between Finnish and Estonian infants : exposure to Acinetobacter may contribute to the allergy gap

Background Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures. Methods We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. Results Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genusAcinetobacterwas more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile ofAcinetobacter lwoffiiwas more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genusAcinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization. Conclusions In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genusAcinetobacterin the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.Peer reviewe