A drop in the circulating concentrations of soluble receptor for advanced glycation end products is associated with seroconversion to autoantibody positivity but not with subsequent progression to clinical disease in children en route to type 1 diabetes.

BACKGROUND: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. METHODS: We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive sample and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. RESULTS: Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. CONCLUSIONS: These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.

Analyses of regulatory CD4+ CD25+ FOXP3+ T cells and observations from peripheral T cell subpopulation markers during the development of type 1 diabetes in children.

Our aim was to study whether the aberrant amount or function of regulatory T cells is related to the development of type 1 diabetes (T1D) in children. We also set out to investigate the balance of different T cell subtype markers during the T1D autoimmune process. Treg cells were quantified with flow cytometric assay, and the suppression capacity was analysed with a carboxyfluorescein succinimidyl ester (CFSE)-based T cell suppression assay in children in various phases of T1D disease process and in healthy autoantibody-negative control children. The mRNA expression of different T cell subpopulation markers was analysed with real-time qPCR method. The proportion and suppression capacity of regulatory T cells were similar in seroconverted children at an early stage of beta cell autoimmunity and also in children with T1D when compared to healthy and autoantibody-negative children. Significant differences were observed in the mRNA expression of different T cell subpopulation markers in prediabetic children with multiple (≥ 2) autoantibodies and in children with newly diagnosed T1D when compared to the control children. In conclusion, there were no quantitative or functional differences in regulatory T cells between the case and control groups in any phase of the autoimmune process. Decreased mRNA expression levels of T cell subtype markers were observed in children with multiple islet autoantibodies and in those with newly diagnosed T1D, probably reflecting an exhaustion of the immune system after the strong immune activation during the autoimmune process or a generally aberrant immune response related to the progression of the disease.

Genetic susceptibility to type 1 diabetes in childhood - estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity.

OBJECTIVE: The HLA-DR/DQ region remains the major determinant of susceptibility to type 1 diabetes (T1D) despite the more than 50 risk affecting loci outside human leukocyte antigen (HLA) region that have been identified. We aimed at developing a simple risk estimation based on HLA class II genotyping, which was also tested by analyzing HLA class II effect on the autoantibody seroconversion and further progression to diabetes. SUBJECTS AND METHODS: A total of 2991 trio families with a diabetic child from the Finnish Pediatric Diabetes Register were genotyped and the risk contributed by each DR-DQ haplotype calculated through transmission analysis. The genotype risk was estimated based on the summary effect of haplotypes. Genotype grouping was further tested in a subcohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study RESULTS: The summary effect of haplotypes was generally seen in genotypes, while the expected synergistic effect of DR3-DQ2 and DR4-DQ8 (DRB1*04:03 excluded) combination was also clear in the T1D risk association analysis. This highest risk DR/DQ genotype was found in 21.6% of patients and 2.0% of controls, odds ratio (OR) = 13.2 (10.1-17.2), whereas the lowest risk genotype contained only 0.8% of patients and 28.0% of controls, OR = 0.02 (0.01-0.03). In the subcohort from the DIPP study the risk grades correlated clearly with seroconversion for islet autoantibodies and T1D development. In contrast, DR/DQ risk groups did not associate with the progression rate from advanced autoimmunity to clinical diabetes. CONCLUSIONS: Class II HLA genotype groups improve the estimation of T1D risk. Class II effect is limited to the early phase of the disease process characterized by seroconversion for islet autoantibodies.

Prevalence of obesity was related to HLA-DQ in 2-4-year-old children at genetic risk for type 1 diabetes.

OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.

No association between vitamin D and ß-cell autoimmunity in Finnish and Estonian children.

BACKGROUND: Vitamin D has immunomodulatory properties, such as regulation of FOXP3 expression and regulatory T-cell activity. Our aim was to investigate whether plasma 25-hydroxyvitamin D [25(OH)D] concentrations associate with the development of ß-cell autoimmunity and the transcriptional activity of FOXP3 or vitamin D3 convertase gene (CYP27B1) in CD4+ memory T cells. METHODS: We studied 83 Finnish and 32 Estonian children participating in the DIABIMMUNE and DIPP studies. Twenty-nine Finnish and six Estonian children tested positive for at least one diabetes-associated autoantibody. The plasma concentrations of 25(OH)D and 1,25(OH)2D were analysed with an enzyme immunoassay. Gene expression of FOXP3 and CYP27B1 in the isolated CD4+ memory T cells was studied with reverse transcription quantitative polymerase chain reaction. RESULTS: Vitamin D status did not differ between subjects positive and negative for ß-cell autoantibodies. Finnish children had higher vitamin D status than Estonian children (p < 0.001). FOXP3 expression was higher in Estonian CD4+ memory T-cell samples than in Finnish samples (p < 0.01) even when including in both groups only children with serum 25(OH)D concentrations in the range of 50-80 nmol/L (p < 0.001). CONCLUSIONS: These findings do not support a crucial role of circulating 25(OH)D as a regulator of ß-cell autoimmunity or FOXP3 expression.

Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes.

AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.

Enterovirus infections in early childhood and the risk of atopic disease--a nested case-control study.

BACKGROUND: Enterovirus infections in childhood have been associated with a reduced risk of atopy in cross-sectional studies. OBJECTIVE: To study the relation between enterovirus infections in the first 2 years of life and atopic disease with IgE sensitization in a prospective study setting. METHODS: This was a nested case-control study among children who had been followed from birth. Neutralizing antibodies against 12 enterovirus serotypes were analysed at the age of 2 years from 71 atopic children and 142 non-atopic control children. Atopy was defined as having an atopic disease and IgE antibodies against at least one aeroallergen by the age of 5 years. RESULTS: Cumulative exposure to different enterovirus serotypes was inversely associated with atopy [odds ratio (OR) 0.73; 95% confidence interval (CI): 0.56-0.96]. The most pronounced protection was seen when echoviruses were analysed as a separate group (OR 0.63; 95%CI: 0.46-0.88). CONCLUSIONS AND CLINICAL RELEVANCE: We propose that exposure to several different enteroviruses in early childhood is inversely associated with atopic diseases. Our results support the hypothesis that repeated microbial infections in early life may protect from atopic sensitization and atopic diseases.

Human parechovirus and the risk of type 1 diabetes.

Human parechoviruses (HPeVs) are RNA viruses associated mainly with mild gastrointestinal and respiratory infections in children and also cause neonatal sepsis and CNS infections. Human enteroviruses, close relatives of HPeVs, associate with the development of type 1 diabetes. In this study, the potential role of HPeV infections in promoting beta cell autoimmunity was investigated by analyzing stool samples of 54 prediabetic case and 134 healthy control children for the presence of HPeV RNA and comparing the derived infection frequencies. All 188 children were participants of the Finnish prospective Diabetes Prediction and Prevention study. Viral RNA was screened for using an HPeV-specific RT-PCR method coupled to liquid hybridization of the PCR product. The overall HPeV infection frequency did not differ between prediabetic case and control children. However, case boys had more HPeV positive samples in the 6-month period before becoming autoantibody positive, when compared to the matching time-period in controls (P < 0.01). HPeV infection at a young age does not appear to play a major role in the development of beta-cell autoimmunity. In boys, however, HPeVs showed time-dependent association with the first detection of diabetes-associated autoantibodies. Thus, in boys, HPeV infections cannot be excluded as a gender-specific risk factor which promotes the development of type 1 diabetes.

Introduction of complementary foods in infancy and atopic sensitization at the age of 5 years: timing and food diversity in a Finnish birth cohort.

OBJECTIVE: To study the associations between timing and diversity of introduction of complementary foods during infancy and atopic sensitization in 5-year-old children. METHODS: In the Finnish DIPP (type 1 diabetes prediction and prevention) birth cohort (n = 3781), data on the timing of infant feeding were collected up to the age of 2 years and serum IgE antibodies toward four food and four inhalant allergens measured at the age of 5 years. Logistic regression was used for the analyses. RESULTS: Median duration of exclusive and total breastfeeding was 1.4 (interquartile range: 0.2-3.5) and 7.0 (4.0-11.0) months, respectively. When all the foods were studied together and adjusted for confounders, short duration of breastfeeding decreased the risk of sensitization to birch allergen; introduction of oats <5.1 months and barley <5.5 months decreased the risk of sensitization to wheat and egg allergens, and oats additionally associated with milk, timothy grass, and birch allergens. Introduction of rye <7.0 months decreased the risk of sensitization to birch allergen. Introduction of fish <6 months and egg ≤11 months decreased the risk of sensitization to all the specific allergens studied. The introduction of <3 food items at 3 months was associated with sensitization to wheat, timothy grass, and birch allergens; the introduction of 1-2 food items at 4 months and ≤4 food items at 6 months was associated with all endpoints, but house dust mite. These results were particularly evident among high-risk children when the results were stratified by atopic history, indicating the potential for reverse causality. CONCLUSIONS: The introduction of complementary foods was consecutively done, and with respect to the timing of each food, early introduction of complementary foods may protect against atopic sensitization in childhood, particularly among high-risk children. Less food diversity as already at 3 months of age may increase the risk of atopic sensitization.

Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.

Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk.

AIMS/HYPOTHESIS: The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to clinical diabetes. METHODS: Children were recruited to the Type 1 Diabetes Prediction and Prevention Project, an ongoing study based on HLA-conferred genetic risk. Autoantibodies against islet cells, insulin, GAD65 and islet antigen 2 were analysed at 3-12 month intervals, starting from birth. RESULTS: During the follow-up, 1,320 children (18.4% of the cohort of 7,165 children) were autoantibody positive in at least one sample. Altogether, 184 autoantibody-positive children progressed to type 1 diabetes. Seroconversion occurred at an early age in the progressors (median 1.5 years), among whom 118 (64%) and 150 (82%) seroconverted to autoantibody positivity before the age of 2 and 3 years, respectively. The incidence of seroconversion peaked at 1 year of age. Compared with other autoantibody-positive children, the median autoantibody levels were already markedly higher 3 to 6 months after the seroconversion in children who later progressed to diabetes. CONCLUSIONS/INTERPRETATION: Early initiation of autoimmunity and rapid increases in autoantibody titres strongly predict progression to overt diabetes before puberty, emphasising the importance of early life events in the development of type 1 diabetes.

Interaction of enterovirus infection and cow's milk-based formula nutrition in type 1 diabetes-associated autoimmunity.

BACKGROUND: Enteral virus infections and early introduction of cow's milk (CM)-based formula are among the suggested triggers of type 1 diabetes (T1D)-associated autoimmunity, although studies on their role have remained contradictory. Here, we aimed to analyse whether interactions between these factors might clarify the controversies. MATERIALS: The study population comprised 107 subjects developing positivity for at least two T1D-associated autoantibodies and 446 control subjects from the Finnish diabetes prediction and prevention cohort. Enterovirus, rotavirus, adenovirus, respiratory syncytial virus and bovine insulin-binding antibodies were analysed from prospective serum samples at 3-24 months of age. Data on infant cow's milk exposure were available for 472 subjects: 251 subjects were exposed to cow's milk before 3 months of age and 221 subjects later in infancy. RESULTS: Signs of an enterovirus infection by 12 months of age were associated with the appearance of autoimmunity among children who were exposed to cow's milk before 3 months of age. Cox regression analysis revealed a combined effect of enterovirus infection and early cow's milk exposure for the development of ICA and any of the biochemically defined autoantibodies (p = 0.001), of IAA (p = 0.002), GADA (p = 0.001) and IA-2A (p = 0.013). CONCLUSIONS: The effect of enterovirus infection on the appearance of T1D-associated autoimmunity seems to be modified by exposure to cow's milk in early infancy suggesting an interaction between these factors. Moreover, these results provide an explanation for the controversial findings obtained when analysing the effect of any single one of these factors on the appearance of T1D-associated autoimmunity.

Maternal dietary fat and fatty acid intake during lactation and the risk of asthma in the offspring.

AIM: To explore the association between maternal dietary fat and fatty acid (FA) intake during lactation, and the risk of asthma in the offspring by the age of 5 years. METHODS: The subjects comprised 1798 mother-child pairs from the Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Dietary intake was assessed by a validated 181-item food frequency questionnaire, which covered the third month of lactation. The cumulative incidence of asthma was assessed at the age of 5 years with a questionnaire modified from the International Study of Asthma and Allergies in Childhood (ISAAC). Cox proportional hazards regression was used for statistical analysis. RESULTS: The maternal use of margarines during lactation was associated with a marginally increased risk of asthma [hazard ratio (HR) for user vs. nonuser 1.96, 95% confidence interval (CI) 1.01-3.82, p = 0.047] after adjusting for putative confounders. The maternal intakes of n-3 polyunsaturated FA (PUFA) and fish during lactation were not associated with the risk of asthma. CONCLUSION: Maternal use of margarines during lactation was weakly associated with an increased risk of asthma in the offspring at the age of 5 years. Other fats or FAs during lactation were not associated with the risk of asthma. However, the nonadherence to dietary recommendations regarding especially fats of our study population may restrict the generalizability of our results.

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes.

AIMS/HYPOTHESIS: This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. METHODS: We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. RESULTS: The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. CONCLUSIONS/INTERPRETATION: These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

Early introduction of root vegetables in infancy associated with advanced ß-cell autoimmunity in young children with human leukocyte antigen-conferred susceptibility to Type 1 diabetes.

AIMS: Early introduction of supplementary foods has been implicated to play a role in the development of ß-cell autoimmunity. We set out to study the effects of breastfeeding and age at introduction of supplementary foods on the development of ß-cell autoimmunity. METHODS: A prospective birth cohort of 6069 infants with HLA-DQB-conferred susceptibility to Type 1 diabetes was recruited between 1996 and 2004. Antibodies against islet cells, insulin, glutamate dehydroxylase and islet antigen 2 were measured at 3- to 12-month intervals. The families recorded at home the age at introduction of new foods and, for each visit, completed a structured dietary questionnaire. The endpoint was repeated positivity for islet cell antibodies plus at least one other antibody and/or clinical Type 1 diabetes (n = 265). RESULTS: Early introduction of root vegetables (by the age of 4 months) was related to increased risk of developing positivity for the endpoint [hazard ratio (95% CI) for the earliest third 1.75 (1.11-2.75) and for the middle third 1.79 (1.22-2.62) compared with the last third (> 4 months), likelihood ratio test P = 0.006], independently of the introduction of other foods and of several putative socio-demographic and perinatal confounding factors. Introducing wheat, rye, oats and/or barley cereals (P = 0.013) and egg (P = 0.031) early was related to an increased risk of the endpoint, but only during the first 3 years of life. CONCLUSIONS: Early introduction of root vegetables during infancy is independently associated with increased risk of ß-cell autoimmunity among Finnish children with increased genetic susceptibility to Type 1 diabetes.

Maternal food consumption during pregnancy and risk of advanced ß-cell autoimmunity in the offspring.

BACKGROUND: Evidence for a putative role of maternal diet during pregnancy in the development of ß-cell autoimmunity in the child is scarce. The authors study the association of food consumption during pregnancy and the development of ß-cell autoimmunity in the offspring. SUBJECTS AND METHODS: A prospective Finnish birth cohort of 4297 infants with human leukocyte antigen (HLA)-DQB1-conferred susceptibility to type 1 diabetes and their mothers. Blood samples were collected from the children at 3-12 months intervals to measure type 1 diabetes-associated antibodies: antibodies against islet cells (ICA), insulin, glutamate dehydroxylase, and islet antigen 2. The mothers completed a validated food frequency questionnaire. The end-point was repeated positivity for ICA together with at least one of the other three antibodies. Piecewise-exponential survival models were used. The effective sample size was 3723, with 138 end-points. The median follow-up time was 4.4 years. RESULTS: Maternal consumption of butter, low-fat margarines, berries, and coffee were inversely associated with the development of advanced ß-cell autoimmunity in the offspring, adjusted for genetic risk group and familial diabetes. These associations for low-fat margarines (use vs. non-use HR 0.60, 95% CI: 0.38-0.93, p = 0.02), berries (continuous variable HR 0.90, 95% CI: 0.83-0.98, p = 0.02) and coffee (highest quarter vs. lowest HR 0.62, 95% CI: 0.40-0.97, p = 0.04), remained significant when adjusting for potential confounding sociodemographic, perinatal, and other dietary factors. CONCLUSIONS: In this study assessing total food consumption of the mother during pregnancy, only few among the 27 food groups tested were weakly related to the development of advanced ß-cell autoimmunity in Finnish children.

The interferon-induced helicase IFIH1 Ala946Thr polymorphism is associated with type 1 diabetes in both the high-incidence Finnish and the medium-incidence Hungarian populations.

AIMS/HYPOTHESIS: The rs1990760 polymorphism (Ala946Thr) of interferon induced with helicase C domain 1 (IFIH1) has been proposed to associate with type 1 diabetes. In this study, association between IFIH1 Ala946Thr and type 1 diabetes was investigated in two distinct white populations, the Hungarians and Finns. METHODS: The rs1990760 polymorphism was genotyped in 757/509 Hungarian/Finnish childhood-onset cases, 499/250 Hungarian/Finnish control individuals and in 529/924 Hungarian/Finnish nuclear family trios. Disease association was tested using case-control and family-based approaches. A meta-analysis of data from 9,546 cases and 11,000 controls was also performed. RESULTS: In the Hungarian dataset, the A allele was significantly more frequent among cases than among controls (OR 1.29, 95% CI 1.10-1.52; p = 0.002). Combined analysis of Hungarian and Finnish datasets revealed a strong disease association (OR 1.235, 95% CI 1.083-1.408; p = 0.002). Furthermore, the A allele was significantly overtransmitted in both family trio datasets (p = 0.017 in Hungarians; p = 0.007 in Finns). The A allele was increased in Hungarian vs Finnish cases (64.9% vs 60.8% in Finns; p = 0.003). The meta-analysis yielded a significant effect for IFIH1 rs1990760 A allele on type 1 diabetes risk (OR 1.176, 95% CI 1.130-1.225; p = 5.3 x 10(-15)) with significant heterogeneity between effect sizes across the studied populations (p = 0.023). CONCLUSIONS/INTERPRETATION: This study represents the first independent confirmation of the association between type 1 diabetes and the IFIH1 gene in Hungarian and Finnish populations. Summarising the data published so far, a clear association between the Ala946Thr polymorphism and type 1 diabetes was detected, with an apparent difference in the contribution to disease susceptibility in different populations of European ancestry.

Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring.

AIMS/HYPOTHESIS: We evaluated the intake of vitamin D by pregnant Finnish women and examined associations between maternal intake of vitamin D and the development of advanced beta cell autoimmunity and type 1 diabetes in their offspring. METHODS: The research was carried out within the Diabetes Prediction and Prevention study (DIPP), which is a population-based birth cohort of infants at genetic risk of type 1 diabetes. Mothers of 3,723 infants born between 1997 and 2002 completed a validated 181-item food frequency questionnaire, which included questions on dietary supplements. The offspring were observed at 3 to 12 month intervals for the appearance of autoantibodies associated with type 1 diabetes and for the development of clinical type 1 diabetes. RESULTS: Maternal mean daily intake of vitamin D was 5.1 microg from food and 1.3 microg from supplements. The maternal intake of vitamin D, either from food or from supplements, was not associated with the risk of advanced beta cell autoimmunity/type 1 diabetes in offspring (HR [95% CI] for intake of vitamin D from food 1.25 [0.80-1.95], for vitamin D intake from supplements 1.05 [0.95-1.16]), or with the risk of type 1 diabetes alone (HR [95% CI] for intake of vitamin D from food 0.84 [0.41-1.72], for vitamin D intake from supplements 1.09 [0.99-1.20]). CONCLUSIONS/INTERPRETATION: Maternal intake of vitamin D either from food or supplements during pregnancy is not associated with advanced beta cell autoimmunity/type 1 diabetes or with type 1 diabetes alone in Finnish offspring carrying increased genetic susceptibility to type 1 diabetes.

Parental and childhood overweight in sedentary and active adolescents.

We studied whether the prevalence of overweight since age 2 years differed in sedentary and active adolescents (N=346). Further, we analyzed the energy intake of sedentary and active adolescents across 12 years. BMI was assessed annually since birth, energy intake since age 13 months and parents' BMI from the time their child was 7 months old in a longitudinal atherosclerosis prevention study. Data on physical activity were collected at age 13 years (N=560). Sedentary and Active groups were formed by upper and lower physical activity tertile cut-points. Girls Sedentary at 13 years were more often overweight than Active peers already since age 2 years (P=0.048). Activity habits were not associated with energy intake. Conversely, among boys, activity habits in adolescence were not associated with childhood overweight, while the energy intake of Active boys was higher than that of Sedentary boys (P=0.008). Parental overweight was not associated with the physical activity of children; however, Sedentary girls more often had an overweight mother than Active girls (P=0.021). In conclusion, overweight during early years of life is more common among girls who are Sedentary as adolescents than in Active peers. Overweight mothers more often have Sedentary daughters than normal-weight mothers. A healthy lifestyle right from early childhood requires active support.

Dietary and lifestyle counselling reduces the clustering of overweight-related cardiometabolic risk factors in adolescents.

AIM: The aim of this study was to evaluate the impact of individualised dietary and lifestyle counselling, primarily aimed to decrease serum low-density lipoprotein cholesterol, on the clustering of overweight-related cardiometabolic risk factors in children. DESIGN AND PARTICIPANTS: The 7-month-old study children were randomized either to counselling (n = 540) or control group (n = 522). MAIN OUTCOME MEASURES: The 5- to 15-year-old participants who fulfilled the international criteria were classified as overweight. Being in the highest [lowest for high-density lipoprotein (HDL) cholesterol] age- and gender-specific quintile of body mass index (BMI), blood pressure, serum triglycerides, HDL cholesterol or glucose was considered a risk factor. A cluster was defined as having high BMI and > or = 2 other risk factors. RESULTS: The counselling did not reduce the prevalence of overweight in 5- to 15-year-old participants. From age 7 onwards, the proportion of children with > or = 2 risk factors was lower in the intervention than in the control group (p = 0.005). At the age of 15 years, 13.0% of girls and 10.8% of boys in the intervention group and 17.5% of girls and 18.8% of boys in the control group had the risk factor cluster (p = 0.046 for main effect of the study group). Having even one risk factor at the age of 5 years predicted the clustering of risk factors at the age of 15 years (OR: 3.8, p < 0.001). CONCLUSION: Repeated, individualized dietary and lifestyle counselling may reduce the clustering of overweight-related cardiometabolic risk factors in adolescents even though the counselling is not intense enough to prevent overweight.