Umbilical cord blood DNA methylation in children who later develop type 1 diabetes

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 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.Peer reviewe

Umbilical cord blood DNA methylation in children who later develop type 1 diabetes

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 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.</p

Association between Dopamine Receptor D2 (DRD2) Variations rs6277 and rs1800497 and Cognitive Performance According to Risk Type for Psychosis : A Nested Case Control Study in a Finnish Population Sample

Background There is limited research regarding the association between genes and cognitive intermediate phenotypes in those at risk for psychotic disorders. Methods We measured the association between established psychosis risk variants in dopamine D2 receptor (DRD2) and cognitive performance in individuals at age 23 years and explored if associations between cognition and these variants differed according to the presence of familial or clinical risk for psychosis. The subjects of the Oulu Brain and Mind Study were drawn from the general population-based Northern Finland 1986 Birth Cohort (NFBC 1986). Using linear regression, we compared the associations between cognitive performance and two candidate DRD2 polymorphisms (rs6277 and rs1800497) between subjects having familial (n=61) and clinical (n=45) risk for psychosis and a random sample of participating NFBC 1986 controls (n=74). Cognitive performance was evaluated using a comprehensive battery of tests at follow-up. Results Principal components factor analysis supported a three-factor model for cognitive measures. The minor allele of rs6277 was associated with poorer performance on a verbal factor (p=0.003) but this did not significantly interact with familial or clinical risk for psychosis. The minor allele of rs1800497 was associated with poorer performance on a psychomotor factor (p=0.038), though only in those at familial risk for psychotic disorders (interaction p=0.049). Conclusion The effect of two DRD2 SNPs on cognitive performance may differ according to risk type for psychosis, suggesting that cognitive intermediate phenotypes differ according to the type (familial or clinical) risk for psychosis.Peer reviewe

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis : the CARTA consortium

Peer reviewe

ClinFlow — an interactive application for clinical data mining

Abstract Analyzing clinical data comes with many challenges. Medical expertise combined with statistical and programming knowledge must go hand-in-hand when applying data mining methods on clinical datasets. This work aims at bridging the gap between clinical expertise and computer science knowledge by providing an application for clinical data analysis with no requirement for statistical programming knowledge. Our tool allows clinical researchers to conduct data processing and visualization in an interactive environment, thus providing an assisting tool for clinical studies. The application was experimentally evaluated with an analysis of Type 1 Diabetes clinical data. The results obtained with the tool are in line with the domain literature, demonstrating the value of our application in data exploration and hypothesis testing

Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups

Abstract Background: Anatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes. Methods: The Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated. Results: We observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups. Conclusion: We report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants:a protocol for three parallel double-blind, randomised controlled trials (INVESTDIA)

Abstract Aims: β-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP − 1) analogue liraglutide in three early stages of type 1 diabetes. Methods: We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10−14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed. Conclusions: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic β-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate

Metformin versus insulin for gestational diabetes:adiposity variables and adipocytokines in offspring at age of 9 years

Abstract Aims: To compare body composition, visceral adiposity, adipocytokines, and low-grade inflammation markers in prepubertal offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). Methods: 172 offspring of 311 mothers randomized to receive metformin (n = 82) or insulin (n = 90) for GDM were studied at 9 years of age (follow-up rate 55%). Measurements included anthropometrics, adipocytokines, markers of the low-grade inflammation, abdominal magnetic resonance imaging (MRI), magnetic liver spectrometry (MRS), and whole body dual-energy X-ray absorptiometry (DXA). Results: Serum markers of low-grade inflammation, visceral adipose tissue volume, total fat percentage, and liver fat percentage were similar between the study groups. Serum adiponectin concentration was higher in children in the metformin group compared to insulin group (median 10.37 vs 9.50 µg/ml, p = 0.016). This difference between groups was observed in boys only (median 12.13 vs 7.50 µg/ml, p &lt; 0.001). Leptin/adiponectin-ratio was lower in boys in the metformin group than in the insulin group (median 0.30 vs 0.75; p = 0.016). Conclusions: Maternal metformin treatment for GDM had no effects on adiposity, body composition, liver fat, or inflammation markers in prepubertal offspring compared to maternal insulin treatment but was associated with higher adiponectin concentration and lower leptin/adiponectin-ratio in boys

Autoantibodies to N-terminally truncated GAD₆₅(96‐585):HLA associations and predictive value for type 1 diabetes

Abstract Objective: To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD₆₅(96‐585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. Methods: In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results: T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2‐61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P &lt; 0.001). Conclusions: Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96‐585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D

First-emerging islet autoantibody and glucose metabolism:search for type 1 diabetes subtypes

Abstract Objectives: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3–12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n  = 143), GAD antibody (GADA) multiple (n  = 126) and islet antigen 2 antibody (IA-2A) multiple (n  = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n  = 87), GADA only (n   = 114) and IA-2A only (n  = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P &lt; 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P &lt; 0.001) and 7% vs 43% (P &lt; 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation