| 1. |
- Anand, Vibha, et al.
(författare)
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Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes : Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44, s. 2269-2276
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes.RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.RESULTS: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively.CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
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| 2. |
- Ghalwash, Mohamed, et al.
(författare)
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Islet autoantibody screening in at-risk adolescents to predict type 1 diabetes until young adulthood : a prospective cohort study
- 2023
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Ingår i: The Lancet Child and Adolescent Health. - 2352-4642. ; 7:4, s. 261-268
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Tidskriftsartikel (refereegranskat)abstract
- Background: Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10−18 years with an increased risk of developing type 1 diabetes. Methods: Data were harmonised from prospective studies from Finland (the Diabetes Prediction and Prevention study), Germany (the BABYDIAB study), and the USA (Diabetes Autoimmunity Study in the Young and the Diabetes Evaluation in Washington study). Autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2 were measured at each follow-up visit. Children who were lost to follow-up or diagnosed with type 1 diabetes before 10 years of age were excluded. Inverse probability censoring weighting was used to include data from remaining participants. Sensitivity and the positive predictive value of these autoantibodies, tested at one or two ages, to predict type 1 diabetes by the age of 18 years were the main outcomes. Findings: Of 20 303 children with an increased type 1 diabetes risk, 8682 were included for the analysis with inverse probability censoring weighting. 1890 were followed up to 18 years of age or developed type 1 diabetes between the ages of 10 years and 18 years, and their median follow-up was 18·3 years (IQR 14·5–20·3). 442 (23·4%) of 1890 adolescents were positive for at least one islet autoantibody, and 262 (13·9%) developed type 1 diabetes. Time from seroconversion to diabetes diagnosis increased by 0·64 years (95% CI 0·34–0·95) for each 1-year increment of diagnosis age (Pearson's correlation coefficient 0·88, 95% CI 0·50–0·97, p=0·0020). The median interval between the last prediagnostic sample and diagnosis was 0·3 years (IQR 0·1–1·3) in the 227 participants who were autoantibody positive and 6·8 years (1·6–9·9) for the 35 who were autoantibody negative. Single screening at the age of 10 years was 90% (95% CI 86–95) sensitive, with a positive predictive value of 66% (60–72) for clinical diabetes. Screening at two ages (10 years and 14 years) increased sensitivity to 93% (95% CI 89–97) but lowered the positive predictive value to 55% (49–60). Interpretation: Screening of adolescents at risk for type 1 diabetes only once at 10 years of age for islet autoantibodies was highly effective to detect type 1 diabetes by the age of 18 years, which in turn could enable prevention of diabetic ketoacidosis and participation in secondary prevention trials. Funding: JDRF International.
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| 3. |
- Hirvonen, M Karoliina, et al.
(författare)
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Serum APOC1 levels are decreased in young autoantibody positive children who rapidly progress to type 1 diabetes
- 2023
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children.
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| 4. |
- Laajala, Essi, et al.
(författare)
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Umbilical cord blood DNA methylation in children who later develop type 1 diabetes
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:Suppl. 1, s. 291-291
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Distinct DNA methylation patterns have recently been observed to precede Type 1 Diabetes in whole blood collected from young children. Our aim was to determine if such methylation patterns are present already at the time of birth. Reduced representation bisulfite sequencing (RRBS) analysis was performed on a unique collection of umbilical cord blood samples collected within the Type 1 Diabetes Prediction and Prevention (DIPP) study. Children later diagnosed with Type 1 Diabetes and/or testing positive for multiple islet autoantibodies (N=43) were compared to control individuals (N=79), who remained autoantibody‐negative throughout the DIPP follow‐up until 15 years of age. Altogether 24 clinical and technical covariates related to the pregnancy and the mother were included in a binomial mixed effects model, which was fit separately for each high‐coverage CpG site, followed by spatial and multiple testing adjustment of P values. We discovered a strong inflation of P values, which was caused by a standard spatial adjustment method. Findings that were based on Benjamini‐Hochberg corrected spatially adjusted P values, could not be validated by Pyrosequencing. We therefore used permutation‐based significance analysis and showed that sex‐associated differentially methylated cytosines could be reproducibly detected with this approach. After empirical type 1 error control, no differences in cord blood methylation patterns were observed between cases and controls. Differences between children who progress to Type 1 Diabetes and those who remain healthy throughout childhood, are not yet present in the perinatal DNA methylome.
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| 5. |
- Laajala, Essi, et al.
(författare)
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Umbilical cord blood DNA methylation in children who later develop type 1 diabetes
- 2022
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 65:9, s. 1534-1540
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine whether perinatal DNA methylation is associated with later progression to type 1 diabetes.METHODS: Reduced representation bisulphite sequencing (RRBS) analysis was performed on umbilical cord blood samples collected within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. Children later diagnosed with type 1 diabetes and/or who tested positive for multiple islet autoantibodies (n = 43) were compared with control individuals (n = 79) who remained autoantibody-negative throughout the DIPP follow-up until 15 years of age. Potential confounding factors related to the pregnancy and the mother were included in the analysis.RESULTS: No differences in the umbilical cord blood methylation patterns were observed between the cases and controls at a false discovery rate <0.05.CONCLUSIONS/INTERPRETATION: Based on our results, differences between children who progress to type 1 diabetes and those who remain healthy throughout childhood are not yet present in the perinatal DNA methylome. However, we cannot exclude the possibility that such differences would be found in a larger dataset.
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| 6. |
- Lamichhane, Santosh, et al.
(författare)
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Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children
- 2023
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Appearance of multiple islet cell autoantibodies in early life is indicative of future progression to overt type 1 diabetes, however, at varying rates. Here, we aimed to study whether distinct metabolic patterns could be identified in rapid progressors (RP, disease manifestation within 18 months after the initial seroconversion to autoantibody positivity) vs. slow progressors (SP, disease manifestation at 60 months or later from the appearance of the first autoantibody).METHODS: Longitudinal samples were collected from RP (n=25) and SP (n=41) groups at the ages of 3, 6, 12, 18, 24, or ≥ 36 months. We performed a comprehensive metabolomics study, analyzing both polar metabolites and lipids. The sample series included a total of 239 samples for lipidomics and 213 for polar metabolites.RESULTS: We observed that metabolites mediated by gut microbiome, such as those involved in tryptophan metabolism, were the main discriminators between RP and SP. The study identified specific circulating molecules and pathways, including amino acid (threonine), sugar derivatives (hexose), and quinic acid that may define rapid vs. slow progression to type 1 diabetes. However, the circulating lipidome did not appear to play a major role in differentiating between RP and SP.CONCLUSION/INTERPRETATION: Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes.
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| 7. |
- Ojwang', Vincent, et al.
(författare)
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Early exposure to cats, dogs and farm animals and the risk of childhood asthma and allergy.
- 2020
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Ingår i: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. - : Wiley. - 1399-3038. ; 31:3, s. 265-272
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Tidskriftsartikel (refereegranskat)abstract
- Synergistic role of exposure to cats, dogs, and farm animals during infancy on the risk of childhood asthma and allergy remains unknown.To investigate independent and synergistic associations between exposure to indoor pets and farm animals during infancy and the risk of asthma and allergy by age 5.We studied 3781 children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) nutrition study. At age 5, a validated version of the International Study of Asthma and Allergies in Childhood questionnaire was administered to collect information on asthma and allergic disease; and exposure to indoor pets and farm animals during the first year of life. Allergen-specific IgE antibodies were analyzed from serum samples. Statistical analyses employed Cox proportional hazards- and logistic regression.Having a dog in the house was inversely associated with the risk of asthma (HR 0.60; 95%CI, 0.38-0.96); allergic rhinitis (OR 0.72; 95%CI, 0.53-0.97); and atopic sensitization (OR 0.77; 95%CI, 0.63-0.96). Having a cat was associated with decreased risk of atopic eczema (OR 0.68; 95%CI, 0.51-0.92). Farm animals were neither independently nor in synergy with indoor pets associated with the outcomes.Having a dog or cat in the house during the first year of life may protect against childhood asthma and allergy. We did not find a synergistic association between cat, dog and farm animal exposure on the risk of childhood asthma and allergy. Future research should identify specific causative exposures conferred by indoor pets and whether they could be recommended for allergy prevention.
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| 8. |
- Sen, Partho, et al.
(författare)
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Metabolic alterations in immune cells associate with progression to type 1 diabetes
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:5, s. 1017-1031
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes.METHODS: In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10).RESULTS: During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression.CONCLUSIONS/INTERPRETATION: Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes.DATA AVAILABILITY: The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/), under accession number MTBLS1015.
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| 9. |
- Sinisalu, Lisanna, 1993-, et al.
(författare)
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Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease
- 2020
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Ingår i: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 188
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Tidskriftsartikel (refereegranskat)abstract
- Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age). Here we analyzed PFAS, BAs and lipidomic profiles in 66 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n = 17 progressors to CD, n = 16 healthy controls, HCs). Plasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD progressors, indicative of different absorption of lipids in these infants. In conclusion, PFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.
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| 10. |
- Stahl, Marisa, et al.
(författare)
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Incidence of Pediatric Celiac Disease Varies by Region
- 2023
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Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 118:3, s. 539-545
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010.METHODS:Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site.RESULTS:Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively.DISCUSSION:There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.
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