Publications by authors named "Mikael Knip"

384 Publications

Breastfeeding and circulating immunological markers during the first 3 years of life: the DIABIMMUNE study.

Diabetologia 2021 Nov 27. Epub 2021 Nov 27.

Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Aims/hypothesis: Our aim was to study the association between duration of breastfeeding and circulating immunological markers during the first 3 years of life in children with HLA-conferred susceptibility to type 1 diabetes.

Methods: We performed a longitudinal analysis of 38 circulating immunological markers (cytokines, chemokines and growth factors) in serum samples from Finnish (56 individuals, 147 samples), Estonian (56 individuals 148 samples) and Russian Karelian children (62 individuals, 149 samples) at 3, 6, 12, 18, 24 and 36 months of age. We also analysed gut inflammation markers (calprotectin and human β defensin-2) at 3 (n = 96) and 6 months (n = 153) of age. Comparisons of immunological marker medians were performed between children who were breastfed for 6 months or longer vs children who were breastfed for less than 6 months.

Results: Breastfeeding for 6 months or longer vs less than 6 months was associated with lower median of serum immunological markers at 6 months (granulocyte-macrophage colony-stimulating factor [GMCSF], macrophage inflammatory protein [MIP-3α]), 12 months (IFN-α2, vascular endothelial growth factor, GMCSF, IFN-γ, IL-21), 18 months (FGF-2, IFN-α2) and 24 months of age (CCL11 [eotaxin], monocyte chemoattractant protein-1, TGFα, soluble CD40 ligand, IL-13, IL-21, IL-5, MIP-1α) (all p < 0.01) but not at 36 months of age. Breastfeeding was not associated with gut inflammation markers at 3 and 6 months of age.

Conclusions/interpretation: Children who were breastfed for 6 months or longer had lower medians for 14 immunological markers at one or more age points during the first 2 years of life compared with children who were breastfed for less than 6 months. The clinical meaning of the findings is not clear. However, the present study contributes to the understanding of immunological differences in children that have been breastfed longer, and thus provides a mechanistic suggestion for the previously observed associations between breastfeeding and risk of type 1 diabetes.
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http://dx.doi.org/10.1007/s00125-021-05612-2DOI Listing
November 2021

Determining the timing of pubertal onset via a multicohort analysis of growth.

PLoS One 2021 18;16(11):e0260137. Epub 2021 Nov 18.

Faculty of Social Sciences, Unit of Health Sciences, Tampere University, Tampere, Finland.

Objective: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing.

Design: This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP).

Methods: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model.

Results: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference.

Conclusions: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601458PMC
November 2021

Maternal energy-adjusted fatty acid intake during pregnancy and the development of cow's milk allergy in the offspring.

Br J Nutr 2021 Nov 12:1-20. Epub 2021 Nov 12.

Faculty of Social Sciences, Unit of Health Sciences, Tampere University, 33014, Tampere, Finland.

Cow's milk allergy (CMA) is one of the earliest manifestations of allergic diseases. Early dietary factors, like maternal diet during pregnancy, may play a role in the development of allergic diseases in the offspring. We aimed to investigate the association between maternal intake of fatty acids during pregnancy and the risk of CMA in the offspring. Our study was conducted in a population-based cohort, the Finnish Type 1 Diabetes Prediction and Prevention study. We collected the maternal dietary data by a validated food frequency questionnaire. We obtained the information on CMA in the study participants (n=448) from registers and from the parents. Dietary data and information on CMA were available for 4921 children. We used logistic regression in the analyses and fatty acid intakes were energy adjusted. The maternal intake of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (PUFA), n-3 PUFA, n-6 PUFA, trans fatty acids, ratio of n-3 PUFA to n-6 PUFA or ratio of linoleic acid to alpha-linolenic acid were not associated with the risk of CMA in the offspring when adjusted for perinatal factors, background factors, parental history of asthma or allergic rhinitis and infant animal contacts. The intake of alpha-linolenic acid was associated with a decreased risk (OR 0.72; 95%CI 0.56-0.93) of CMA in the offspring of mothers without a history of allergic rhinitis or asthma. In conclusion the maternal intake of fatty acids during pregnancy is not associated with the risk of CMA in the offspring.
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http://dx.doi.org/10.1017/S0007114521004475DOI Listing
November 2021

Autoantibodies to N-Terminally Truncated GAD65(96-585): HLA Associations and Predictive Value for Type 1 Diabetes.

J Clin Endocrinol Metab 2021 Nov 8. Epub 2021 Nov 8.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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 HLA-associations with such autoantibodies.

Design: In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention (DIPP) Study, the DIABIMMUNE Study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity (EDIA) 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 years (range 0.2-61.5). 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<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.
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http://dx.doi.org/10.1210/clinem/dgab816DOI Listing
November 2021

Exposure to per- and polyfluoroalkyl substances associates with an altered lipid composition of breast milk.

Environ Int 2021 12 6;157:106855. Epub 2021 Sep 6.

School of Science and Technology, Örebro University, 702 81 Örebro, Sweden. Electronic address:

The composition of human breast milk is highly variable inter- and intra-individually. Environmental factors are suspected to contribute to such compositional variation, however, their impact on breast milk composition is currently poorly understood. We sought to (1) define the impact of maternal exposure to per- and polyfluoroalkyl substances (PFAS) on lipid composition of human breast milk, and (2) to study the combined impact of maternal PFAS exposure and breast milk lipid composition on the growth of the infants.In a mother-infant study (n = 44) we measured the levels of PFAS and lipids in maternal serum and conducted lipidomics analysis of breast milk collect 2-4 days after the delivery and at 3 months of infant age, by using ultra high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry. Gastrointestinal biomarkers fecal calprotectin and human beta defensin 2 were measured in the stool samples at the age of 3, 6, 9, and 12 months. Maternal diet was studied by a validated food frequency questionnaire. PFAS levels were inversely associated with total lipid levels in the breast milk collected after the delivery. In the high exposure group, the ratio of acylated saturated and polyunsaturated fatty acids in triacylglycerols was increased. Moreover, high exposure to PFAS associated with the altered phospholipid composition, which was indicative of unfavorable increase in the size of milk fat globules. These changes in the milk lipid composition were further associated with slower infant growth and with elevated intestinal inflammatory markers. Our data suggest that the maternal exposure to PFAS impacts the nutritional quality of the breast milk, which, in turn, may have detrimental impact on the health and growth of the children later in life.
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http://dx.doi.org/10.1016/j.envint.2021.106855DOI Listing
December 2021

Frailty modeling under a selective sampling protocol: an application to type 1 diabetes related autoantibodies.

Stat Med 2021 Dec 8;40(28):6410-6420. Epub 2021 Sep 8.

Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.

In studies following selective sampling protocols for secondary outcomes, conventional analyses regarding their appearance could provide misguided information. In the large type 1 diabetes prevention and prediction (DIPP) cohort study monitoring type 1 diabetes-associated autoantibodies, we propose to model their appearance via a multivariate frailty model, which incorporates a correlation component that is important for unbiased estimation of the baseline hazards under the selective sampling mechanism. As further advantages, the frailty model allows for systematic evaluation of the association and the differences in regression parameters among the autoantibodies. We demonstrate the properties of the model by a simulation study and the analysis of the autoantibodies and their association with background factors in the DIPP study, in which we found that high genetic risk is associated with the appearance of all the autoantibodies, whereas the association with sex and urban municipality was evident for IA-2A and IAA autoantibodies.
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http://dx.doi.org/10.1002/sim.9190DOI Listing
December 2021

Consumption of differently processed milk products and the risk of asthma in children.

Pediatr Allergy Immunol 2021 Sep 2. Epub 2021 Sep 2.

Public Health and Welfare Department, Finnish Institute for Health and Welfare, Helsinki, Finland.

Background: Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort.

Methods: We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)-based classifications for milk products. The data were analyzed using a joint model for longitudinal and time-to-event data.

Results: At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat-treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat-treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction.

Conclusions: High consumption of infant formula and other strongly heat-treated milk products may be associated with the development of asthma.
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http://dx.doi.org/10.1111/pai.13659DOI Listing
September 2021

Dietary compliance in a randomized double-blind infant feeding trial during infancy aiming at prevention of type 1 diabetes.

Food Sci Nutr 2021 Aug 23;9(8):4221-4231. Epub 2021 Jun 23.

University of Helsinki Helsinki Finland.

The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis whether extensively hydrolyzed casein-based versus regular cow's milk-based infant formula reduces the risk of type 1 diabetes. We describe dietary compliance in the trial in terms of study formula intake, feeding of nonrecommended foods, and serum cow's milk antibody concentration reflecting intake of cow's milk protein among 2,159 eligible newborn infants with a biological first-degree relative affected by type 1 diabetes and with HLA-conferred susceptibility to type 1 diabetes. The participating infants were introduced to the study formula feeding at the median age of 15 days with a median duration of study formula use of 63 days. During the intervention, 80% of the infants received study formula. Of these, 57% received study formula for at least 2 months. On average, 45.5 l of study formula were used per infant. Only 13% of the population had received a nonrecommended food by the age of 6 months. The dietary compliance was similar in the intervention and control arm. The reported cow's milk consumption by the families matched very well with measured serum casein IgA and IgG antibody concentration. To conclude, good compliance was observed in this randomized infant feeding trial. Compliance varied between the regions and those infants who were breastfed for a longer period of time had a shorter exposure to the study formula. High dietary compliance in infant feeding trial is necessary to allow accurate interpretation of study results.
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http://dx.doi.org/10.1002/fsn3.2389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358383PMC
August 2021

Higher circulating EGF levels associate with a decreased risk of IgE sensitization in young children.

Pediatr Allergy Immunol 2021 Aug 11. Epub 2021 Aug 11.

Research Program for Translational Immunology, University of Helsinki, Helsinki, Finland.

Background: Decreased exposure to microbial agents in industrialized countries and urban living areas is considered as a risk factor of developing immune-mediated diseases, such as allergies and asthma. Epithelial surfaces in the gastrointestinal and respiratory tracts and in the skin constitute the primary areas in contact with the environmental microbial load.

Methods: We analyzed the levels of 30 cytokines and growth factors in serum or plasma as markers of the immune maturation in the participants in the DIABIMMUNE study from Russian Karelia (n = 60), Estonia (n = 83) and Finland (n = 89), three neighboring countries with remarkable differences in the incidences of allergies, asthma and autoimmune diseases.

Results: We observed an upregulation of T helper cell signature cytokines during the first 12 months of life, reflecting natural development of adaptive immune responses. During the first years of life, circulating concentrations of epidermal growth factor (EGF) were significantly higher, especially in Russian children compared with Finnish children. The children who developed IgE sensitization showed lower levels of EGF than those without such responses.

Conclusion: Our results suggest that low circulating EGF levels associate with the risk of allergies possibly via the effects on the epithelial integrity and mucosal homeostasis.
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http://dx.doi.org/10.1111/pai.13613DOI Listing
August 2021

Increasing plasma glucose before the development of type 1 diabetes-the TRIGR study.

Pediatr Diabetes 2021 11 7;22(7):974-981. Epub 2021 Sep 7.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: The β-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children.

Research Design And Methods: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately.

Results: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp <0.001) and the development of diabetes (p < 0.002 resp <0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003).

Conclusions: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes.
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http://dx.doi.org/10.1111/pedi.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530903PMC
November 2021

Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population.

Hum Immunol 2021 Jul 23. Epub 2021 Jul 23.

Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Electronic address:

Genes in the HLA class II region include the most important inherited risk factors for type 1 diabetes (T1D) although also polymorphisms outside the HLA region modulate the predisposition to T1D. This study set out to confirm a recent observation in which a novel expression quantitative trait locus was formed by three single nucleotide polymorphisms (SNP) in the intron of HLA-DRA1 in DR3-DQ2 haplotypes. The SNPs significantly increased the risk for T1D in DR3-DQ2 homozygous individuals and we intended to further explore this association, in the Finnish population, by comparing two DR3-DQ2 positive genotypes. Cohorts with DR3-DQ2/DR3-DQ2 (N = 570) and DR3-DQ2/DR1-DQ5 (N = 1035) genotypes were studied using TaqMan analysis that typed for rs3135394, rs9268645 and rs3129877. The tri-SNP haplotype was significantly more common in cases than controls in the DR3-DQ2/DR3-DQ2 cohort (OR = 1.70 CI 95% = 1.15-2.51P = 0.007). However, no significant associations could be observed in the DR3-DQ2/DR1-DQ5 cohort.
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http://dx.doi.org/10.1016/j.humimm.2021.07.010DOI Listing
July 2021

Effect of Early Feeding on Intestinal Permeability and Inflammation Markers in Infants with Genetic Susceptibility to Type 1 Diabetes: A Randomized Clinical Trial.

J Pediatr 2021 Nov 20;238:305-311.e3. Epub 2021 Jul 20.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland. Electronic address:

Objectives: To assess whether weaning to an extensively hydrolyzed formula (EHF) decreases gut permeability and/or markers of intestinal inflammation in infants with HLA-conferred diabetes susceptibility, when compared with conventional formula.

Study Design: By analyzing 1468 expecting biological parent pairs for HLA-conferred susceptibility for type 1 diabetes, 465 couples (32 %) potentially eligible for the study were identified. After further parental consent, 332 babies to be born were randomized at 35th gestational week. HLA genotyping was performed at birth in 309 infants. Out of 87 eligible children, 73 infants participated in the intervention study: 33 in the EHF group and 40 in the control group. Clinical visits took place at 3, 6, 9, and 12 months of age. The infants were provided either EHF or conventional formula whenever breastfeeding was not available or additional feeding was required over the first 9 months of life. The main outcome was the lactulose to mannitol ratio (L/M ratio) at 9 months. The secondary outcomes were L/M ratio at 3, 6, and 12 months of age, and fecal calprotectin and human beta-defensin 2 (HBD-2) levels at each visit.

Results: Compared with controls, the median L/M ratio was lower in the EHF group at 9 months (.006 vs .028; P = .005). Otherwise, the levels of intestinal permeability, fecal calprotectin, and HBD-2 were comparable between the two groups, although slight differences in the age-related dynamics of these markers were observed.

Conclusions: It is possible to decrease intestinal permeability in infancy through weaning to an extensively hydrolyzed formula. This may reduce the early exposure to dietary antigens.

Trial Registration: Clinicaltrials.gov: NCT01735123.
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http://dx.doi.org/10.1016/j.jpeds.2021.07.042DOI Listing
November 2021

Association of different enteroviruses with atopy and allergic diseases in early childhood.

Pediatr Allergy Immunol 2021 Nov 16;32(8):1629-1636. Epub 2021 Jul 16.

Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood.

Methods: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1-5 years of age and assessed their association with allergic sensitization and disease.

Results: The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36-0.99), p = .048.

Conclusion: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.
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http://dx.doi.org/10.1111/pai.13577DOI Listing
November 2021

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.

Diabetes Care 2021 Jun 23. Epub 2021 Jun 23.

PEDEGO Research Unit, Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland.

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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http://dx.doi.org/10.2337/dc20-1836DOI Listing
June 2021

New-onset type 1 diabetes in Finnish children during the COVID-19 pandemic.

Arch Dis Child 2021 May 27. Epub 2021 May 27.

New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Viral infections may trigger type 1 diabetes (T1D), and recent reports suggest an increased incidence of paediatric T1D and/or diabetic ketoacidosis (DKA) during the COVID-19 pandemic.

Objective: To study whether the number of children admitted to the paediatric intensive care unit (PICU) for DKA due to new-onset T1D increased during the COVID-19 pandemic, and whether SARS-CoV-2 infection plays a role.

Methods: This retrospective cohort study comprises two datasets: (1) children admitted to PICU due to new-onset T1D and (2) children diagnosed with new-onset T1D and registered to the Finnish Pediatric Diabetes Registry in the Helsinki University Hospital from 1 April to 31 October in 2016-2020. We compared the incidence, number and characteristics of children with newly diagnosed T1D between the prepandemic and pandemic periods.

Results: The number of children admitted to PICU due to new-onset T1D increased from an average of 6.25 admissions in 2016-2019 to 20 admissions in 2020 (incidence rate ratio [IRR] 3.24 [95% CI 1.80 to 5.83]; p=0.0001). On average, 57.75 children were registered to the FPDR in 2016-2019, as compared with 84 in 2020 (IRR 1.45; 95% CI 1.13 to 1.86; p=0.004). 33 of the children diagnosed in 2020 were analysed for SARS-CoV-2 antibodies, and all were negative.

Conclusions: More children with T1D had severe DKA at diagnosis during the pandemic. This was not a consequence of SARS-CoV-2 infection. Instead, it probably stems from delays in diagnosis following changes in parental behaviour and healthcare accessibility.
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http://dx.doi.org/10.1136/archdischild-2020-321220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172262PMC
May 2021

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes.

Diabetes Care 2021 07 5;44(7):1506-1514. Epub 2021 May 5.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

Objective: Environmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.

Research Design And Methods: Association between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes ( = 271) or multiple diabetes-associated islet autoantibodies ( = 384) and children without diabetes who are negative for diabetes autoantibodies.

Results: Agricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16-0.87, = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, = 0.001) compared with an urban environment known to have lower environmental microbial diversity.

Conclusions: The study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.
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http://dx.doi.org/10.2337/dc20-1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323192PMC
July 2021

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study.

Nutrients 2021 Mar 13;13(3). Epub 2021 Mar 13.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, FI-33014 Tampere, Finland.

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring's risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997-2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.
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http://dx.doi.org/10.3390/nu13030928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001228PMC
March 2021

Type 1 diabetes in Finland: past, present, and future.

Authors:
Mikael Knip

Lancet Diabetes Endocrinol 2021 05 12;9(5):259-260. Epub 2021 Mar 12.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, FI-00290 Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, FI-33520 Tampere, Finland. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(21)00074-7DOI Listing
May 2021

Generation of self-reactive, shared T-cell receptor α chains in the human thymus.

J Autoimmun 2021 05 27;119:102616. Epub 2021 Feb 27.

Research Programs Unit, Translational Immunology, and Medicum, University of Helsinki, Haartmaninkatu 3, 00290, Helsinki, Finland.

The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRβ chains with the estimated total TCR diversity of >10. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4 compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRβ repertoire associated with these chains.
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http://dx.doi.org/10.1016/j.jaut.2021.102616DOI Listing
May 2021

Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life.

Front Immunol 2020 11;11:567046. Epub 2021 Feb 11.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.
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http://dx.doi.org/10.3389/fimmu.2020.567046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905218PMC
May 2021

Letter to the Editor from Pöllänen et al: "Birth Cohorts in Type 1 Diabetes: Preparing for the Payoff".

J Clin Endocrinol Metab 2021 08;106(9):e3787-e3788

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland.

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http://dx.doi.org/10.1210/clinem/dgab109DOI Listing
August 2021

Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study.

Front Immunol 2020 2;11:604529. Epub 2021 Feb 2.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections were more frequent in case children before the appearance of celiac disease-associated tissue transglutaminase autoantibodies compared to the corresponding period in control children (OR 6.3, 95% CI 1.8-22.3; p = 0.005). No difference was observed in the frequency of adenovirus infections. The findings suggest that enterovirus infections may contribute to the process leading to celiac disease.
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http://dx.doi.org/10.3389/fimmu.2020.604529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884453PMC
June 2021

Allergy-Related Symptoms Are Poorly Predicted by IgE and Skin Prick Testing in Early Life.

Int Arch Allergy Immunol 2021 5;182(7):574-584. Epub 2021 Feb 5.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland,

Introduction: In childhood, the so-called allergic march involves progression from IgE sensitization to allergy-related symptoms. Both IgE sensitization and relevant clinical symptoms are required for the diagnosis of allergy, but concordance between test results and clinical symptoms varies greatly, creating challenges for the diagnostics and for the prediction of outcomes. We assessed the prevalence of IgE sensitization and allergy symptoms, concordance between 2 IgE sensitization testing methods, and predictive value of these tests in relation to clinical symptoms in young Finnish children.

Methods: The current study included 2 series of children: a birth cohort, in which the participants were followed prospectively from birth up to 3 years, and a young children cohort observed from 3 to 5 years of age. They were regularly monitored for sensitization by measuring serum allergen-specific IgEs (sIgEs) and performing skin prick tests (SPTs). The emergence of atopic dermatitis, wheezing, and symptoms associated with food allergies was recorded.

Results: Over the first 5 years of life, the prevalence of sIgE sensitization was 46%, while it was 36% for positive SPTs. Disease prevalence was 26% for atopic dermatitis, 25% for wheezing, and 19% for symptoms associated with food allergies. Concordance between sIgE and SPT results was good for aeroallergens, but poor for dietary allergens. The association between clinical symptoms and sensitization was stronger at 5 years than at 3 years of age. The proportion of children with concordant combinations of allergy symptoms and sensitization markers in contrast to those with discordant combinations increased from 3 to 5 years.

Conclusion: In early childhood, testing for IgE sensitization predicts allergy-related symptoms in an age-dependent manner, but not particularly well. Tests predict symptoms caused by aeroallergens clearly better than those caused by dietary allergens. The clinical relevance of sensitization testing in early life is therefore limited in the prediction of true allergy.
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http://dx.doi.org/10.1159/000512109DOI Listing
September 2021

Serum fatty acids and risk of developing islet autoimmunity: A nested case-control study within the TRIGR birth cohort.

Pediatr Diabetes 2021 06 24;22(4):577-585. Epub 2021 Feb 24.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.

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.
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http://dx.doi.org/10.1111/pedi.13189DOI Listing
June 2021

Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk.

Diabetologia 2021 04 21;64(4):826-835. Epub 2021 Jan 21.

Pediatrics Epidemiology Center, University of South Florida, Tampa, FL, USA.

Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes.

Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10-14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05.

Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling.

Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2-10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes.

Trial Registration: ClinicalTrials.gov NCT00179777.
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http://dx.doi.org/10.1007/s00125-020-05358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940594PMC
April 2021

Effect of extensively hydrolyzed casein vs. conventional formula on the risk of asthma and allergies: The TRIGR randomized clinical trial.

Pediatr Allergy Immunol 2021 05 27;32(4):670-678. Epub 2021 Jan 27.

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Background: The role of hydrolyzed infant formulas in the prevention of asthma and allergies remains inconsistent. We tested whether extensively hydrolyzed casein formula compared to conventional cow's milk-based formula prevented asthma, allergic rhinitis, or atopic eczema.

Methods: In the randomized double-blind Trial to Reduce IDDM in Genetically at Risk (TRIGR), comparing extensively hydrolyzed to standard cow's milk-based infant formula during the first 6-8 months of life, we assessed the effect of the intervention on the incidence of asthma, allergic rhinitis, and eczema when the children were 9- to 11-years old. The asthma, allergic rhinitis, and eczema occurrence was assessed using online standardized and validated ISAAC questionnaire. Of the 1106 children who participated in this Ancillary study, 560 had been randomized to the experimental (extensively hydrolyzed casein formula) and 546 to the control arm (cow's milk-based formula).

Results: The risk of persistent asthma, allergic rhinitis, or atopic eczema did not differ by treatment, the hazard ratios (95% CI) being 1.00 (0.66-1.52), 0.95 (0.66-1.38), and 0.89 (0.70-1.15), respectively, in the intention-to-treat analysis. Neither were there any differences in the per-protocol analysis.

Conclusions: Extensively hydrolyzed casein formula did not protect from asthma, rhinitis, or eczema in this population carrying genetic risk for type 1 diabetes.
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http://dx.doi.org/10.1111/pai.13452DOI Listing
May 2021

Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children.

Am J Clin Nutr 2021 02;113(2):380-390

Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: Insulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children.

Objectives: The objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting.

Methods: We analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6-36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration.

Results: The mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P < 0.01]. Among 18-mo-old Malawians, plasma IGF-I concentration was inversely associated with systemic inflammation, malaria parasitemia, and intestinal Shigella, Campylobacter, and enterovirus infection and positively associated with the children's weight-for-length z score (WLZ), female sex, maternal height, mother's education, and dry season. Seasonally, mean plasma IGF-I concentration was highest in June and July and lowest in December and January, coinciding with changes in children's length gain and preceded by ∼2 mo by the changes in their WLZ.

Conclusions: The mean plasma IGF-I concentrations are similar in Malawi and Finland among 6-mo-old infants. Thereafter, mean concentrations rise markedly in Finland but not in Malawi. Systemic inflammation and clinically nonapparent infections are strongly associated with lower plasma IGF-I concentrations in Malawi through direct and indirect pathways.
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http://dx.doi.org/10.1093/ajcn/nqaa327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851819PMC
February 2021

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

Diabetologia 2021 03 17;64(3):581-590. Epub 2020 Dec 17.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.
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http://dx.doi.org/10.1007/s00125-020-05342-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864815PMC
March 2021

Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.

Diabetologia 2021 01 7;64(1):119-128. Epub 2020 Oct 7.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Aims/hypothesis: The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility.

Methods: In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member.

Results: Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity.

Conclusions/interpretation: The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth.

Trial Registration: ClinicalTrials.gov NCT00179777 Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05287-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716821PMC
January 2021
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