[Show abstract][Hide abstract] ABSTRACT: Background/objectives:
Diet during pregnancy and lactation may have a role in the development of allergic diseases. There are few human studies on the topic, especially focusing on food allergies. We sought to study the associations between maternal diet during pregnancy and lactation and cow's milk allergy (CMA) in offspring.
A population-based birth cohort with human leukocyte antigen-conferred susceptibility to type 1 diabetes was recruited in Finland between 1997 and 2004 (n=6288). Maternal diet during pregnancy and lactation was assessed by a validated, 181-item semi-quantitative food frequency questionnaire. Register-based information on diagnosed CMA was obtained from the Social Insurance Institution and completed with parental reports. The associations between maternal food consumption and CMA were assessed using logistic regression, comparing the highest and the lowest quarters to the middle half of consumption.
Consumption of milk products in the highest quarter during pregnancy was associated with a lower risk of CMA in offspring (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.37-0.86; P<0.01). When stratified by maternal allergic rhinitis and asthma, there was evidence of an inverse association between high use of milk products and CMA in offspring of non-allergic mothers (OR 0.30, 95% CI 0.13-0.69, P<0.001). Cord blood IgA correlated positively with the consumption of milk products during pregnancy, indicating exposure to CMA and activation of antigen-specific immunity in the infant during pregnancy.
High maternal consumption of milk products during pregnancy may protect children from developing CMA, especially in offspring of non-allergic mothers.European Journal of Clinical Nutrition advance online publication, 13 January 2016; doi:10.1038/ejcn.2015.223.
No preview · Article · Jan 2016 · European journal of clinical nutrition
[Show abstract][Hide abstract] ABSTRACT: Context:
The role of vitamin D in the development of type 1 diabetes (T1D) remains controversial.
To study whether there are detectable differences in serum 25-hydroxyvitamin D (25OHD) concentrations between children who later progressed to T1D (cases) and matched children who remained non-diabetic and negative for islet autoantibodies (controls) when followed from birth until disease onset.
A total of 3702 prospective serum samples from 252 children were measured for 25(OH)D from the age of 3 months onwards using an enzyme immunoassay. Differences between the groups were compared by mixed model analysis of variance.
Type 1 Diabetes Prediction and Prevention study (DIPP) clinics in Turku, Oulu and Tampere University Hospitals, Finland.
By the end of 2012 all 126 case children were diagnosed with T1D. The control children (N=126) were matched for age, sex, study site and HLA-DQ-conferred risk for T1D.
Main outcome measure:
Median circulating 25(OH)D concentration (nmol/L).
The patterns of variation in circulating 25(OH)D concentrations were similar between cases and controls and did not correlate with the age at seroconversion to autoantibody positivity (P= 0.79) or disease onset (P= 0.13). The median concentration of all collected samples did not differ between case and control children (66.6 nmol/L [range 14.0-262.8] vs. 67.4 nmol/L [range 19.9-213.0]), (P= 0.56).
This study shows that serum 25(OH)D concentrations are not associated with the development of T1D in Finland.
No preview · Article · Dec 2015 · Journal of Clinical Endocrinology & Metabolism
[Show abstract][Hide abstract] ABSTRACT: Objective:
We aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity.
Design and methods:
A large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (≥2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors).
In the progressors, the first phase insulin response (FPIR) was decreased as early as 4-6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28-75%) and at 10 years: difference 172% (95% CI 128-224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17-58%) and at 10 years: difference 186% (95% CI 143-237%)). Insulin sensitivity did not differ between the groups.
FPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in β-cell mass and/or function.
No preview · Article · Nov 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study assessed the relationship between autoantibodies against zinc transporter 8 (ZnT8A) and disease characteristics at diagnosis of type 1 diabetes and during the first 2 years.
Research design and methods:
Children, younger than 15 years of age (n = 723) newly diagnosed with diabetes, were analyzed for ZnT8A, other diabetes-associated autoantibodies, HLA DR-DQ alleles, and metabolic status, which was monitored by pH, plasma glucose, and occurrence of ketoacidosis at diagnosis and through follow-up of C-peptide concentrations, exogenous insulin dose, and glycosylated hemoglobin for two years after the diagnosis.
ZnT8A-positivity was detected in 530 children (73%). Positivity for ZnT8A was associated with older age (median 8.9 vs. 8.2 years, P = 0.002) and more frequent ketoacidosis (24% vs. 15%, P = 0.013). Children carrying the HLA DR3 allele were less often ZnT8A positive (66% vs. 77%, P = 0.002) than others. ZnT8A-positive children had lower serum C-peptide concentrations (P = 0.008) and higher insulin doses (P = 0.012) over time than their ZnT8A-negative peers.
Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Human bocaviruses (HBoVs) 1–4 are recently discovered, antigenically similar parvoviruses. We examined the hypothesis that the antigenic similarity of these viruses could give rise to clinically and diagnostically important immunological interactions. IgG and IgM EIAs as well as qPCR were used to study ~2000 sera collected from infancy to early adolescence at 3–6-month intervals from 109 children whose symptoms were recorded. We found that HBoV1-4-specific seroprevalences at age 6 years were 80%, 48%, 10%, and 0%, respectively. HBoV1 infections resulted in significantly weaker IgG responses among children who had pre-existing HBoV2 IgG, and vice versa. Furthermore, we documented a complete absence of virus type-specific immune responses in six viremic children who had pre-existing IgG for another bocavirus, indicating that not all HBoV infections can be diagnosed serologically. Our results strongly indicate that interactions between consecutive HBoV infections affect HBoV immunity via a phenomenon called “original antigenic sin”, cross-protection, or both; however, without evident clinical consequences but with important ramifications for the serodiagnosis of HBoV infections. Serological data is likely to underestimate human exposure to these viruses.
[Show abstract][Hide abstract] ABSTRACT: SETTING: Complications arising from bacille Calmette-Guérin (BCG) vaccination were recorded in a national register in Finland until 1988. In the period 1960–1988, 222 patients suffered from BCG osteitis.
OBJECTIVE: To evaluate whether single nucleotide polymorphisms (SNPs) in the promoter region of the gene encoding interleukin 10 (IL-10) are associated with BCG osteitis after vaccination in neonates.
DESIGN: Blood samples of 132 former BCG osteitis patients now aged 21–49 years were analysed in a controlled study for IL10 rs1800896 (−1082G/A), rs1800871 (−819C/T), rs1800872 (−592C/A) and rs1800890 (−3575T/A) polymorphisms.
RESULTS: The frequencies of genotypes of IL10 rs1800896, rs1800871, rs1800872 and rs1800890, the frequencies of variant genotypes and the frequencies of major or minor alleles did not differ between patients and controls. Furthermore, the frequencies of the eight possible combinations of the three IL10 alleles located close to each other (IL10 rs1800896, IL10 rs1800871 and IL10 rs1800872) were surprisingly similar.
CONCLUSION: Our results suggest that polymorphisms of the IL-10 encoding gene do not play a central role in the development of complications due to BCG vaccination, although the IL10 gene, especially IL10 rs1800896 (−1082G/A) polymorphism, is known to be associated with tuberculosis risk in Europeans and North Americans.
No preview · Article · Sep 2015 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: Viral infections have long been considered potential triggers of beta cell autoimmunity and type 1 diabetes. Recent studies have suggested that influenza A virus might increase the risk of type 1 diabetes. The present study evaluates this risk association in prospectively observed children at the time when islet autoimmunity starts and autoantibodies are first detected.
IgG class antibodies to influenza A virus were analysed in 95 case children whose antibody screening test turned permanently positive for two or more islet autoantibodies and from 186 autoantibody-negative and non-diabetic control children who were matched for time of birth, sex, date of sampling and HLA-conferred risk of diabetes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Virus antibodies were measured from the first autoantibody-positive sample using an enzyme immunoassay. None of the children had been vaccinated against influenza A.
The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units). A similar result was obtained when case and control children were compared separately in subgroups according to different sex, age and HLA-DQ genotype. However, girls had higher antibody levels than boys among both case and control children (median antibody levels 9.0 vs 2.3 enzyme immunoassay units; p = 0.01).
Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD).
291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3-4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4(+) T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-based in vitro proliferation assay.
The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively.
Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD.
[Show abstract][Hide abstract] ABSTRACT: We assessed the utility of the OGTT and random plasma glucose concentrations in predicting the time to diagnosis of type 1 diabetes.
A population-derived cohort of 14,876 newborns with HLA-conferred risk of type 1 diabetes were invited to regular follow-up for islet autoantibodies. When two or more autoantibodies were detected, an OGTT was performed once a year and random plasma glucose analysed twice a year. During follow-up, 567 children developed multiple autoantibodies, 255 (45%) of whom were diagnosed with type 1 diabetes, while 312 remained non-diabetic by December 2011.
Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were risk factors for type 1 diabetes (HR 3.2 [95% CI 1.5, 7.0] and 8.3 [95% CI 6.0, 11.5], respectively). When a random plasma glucose value ≥7.8 mmol/l was observed, the HR for diabetes was 6.0 (95% CI 4.3, 8.6). The median time to diagnosis after the detection of IFG was 5.2 years (interquartile range [IQR] 3.4, 6.3); after IGT, 0.7 years (IQR 0.3, 1.9); and, after a random plasma glucose ≥7.8 mmol/l, 1.0 years (IQR 0.3, 1.5). In a retrospective analysis, both OGTT-derived 2 h plasma glucose and random plasma glucose started to increase 1.5 years before diagnosis (p < 0.001 and p = 0.004, respectively).
Dysglycaemia detected in an OGTT or based on random plasma glucose is a useful marker in the prediction of time to onset of type 1 diabetes in high-risk children. Random plasma glucose is a simple and low-cost measurement with comparable predictive characteristics to that of OGTT-derived 2 h glucose.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE:
This study aimed at investigating the role of IGF-I and IGF binding protein 3 (IGFBP-3) in the development of β-cell autoimmunity.
Five hundred sixty-three subjects with HLA-conferred susceptibility to type 1 diabetes were monitored for signs of seroconversion to positivity for insulin and/or GAD, IA-2, and ZnT8 autoantibodies by the age of 3 years. In 40 subjects who developed at least one autoantibody, IGF-I and IGFBP-3 plasma concentrations were measured and compared with 80 control subjects who remained negative for autoantibodies, and were matched for age, sex, country of origin, and HLA genotype. The increment of IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio before and after seroconverison was compared with corresponding time intervals in controls.
The IGF-I concentrations at the age of 12 months, and the IGF-I/IGFBP-3 ratio at the age of 24 months were lower in the autoantibody-positive children (P <0.05). The increase in circulating IGFBP-3 was significantly higher in the autoantibody-positive children before seroconversion than in the corresponding time-intervals in controls (0.43 mg/l; 95% CI 0.29-0.56 vs. 0.22 mg/l; 95% CI 0.10-0.34 mg/l; P <0.01). Children carrying the high-risk HLA genotype had lower plasma IGF-I and IGFBP-3 concentrations at the age of 24 months than those with low-risk genotypes (P < 0.05 and < 0.01, respectively).
Circulating IGF-I and IGFBP-3 appear to have a role in early development of β-cell autoimmunity. The decreased IGF-I concentrations in children with the high-risk HLA genotype may contribute to the reduced growth previously described in such children.
No preview · Article · May 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip.
After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within -5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm.
This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
[Show abstract][Hide abstract] ABSTRACT: Objective Some studies have compared the occurrence of croup with air pollution. Results have so far remained contradictory. Motor vehicles represent the principal source of air pollution in the city of Vinnytsya, Ukraine. The objective of this study was to determine the relation of traffic load to traffic-dependent pollutants and croup.
Methods Among a population of 8.067 children in residence near areas of high traffic density (>1.500 motor vehicles/ hour) and 2.473 children in residence near areas of low traffic density (<300 motor vehicles/ hour) cases of croup were registered by physicians during a 4 years period in 2000–03. Air pollution by sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter, carbon monoxide (CO) were locally measured.
Results Areas with high traffic load are characterised by higher concentration of traffic-dependent pollutants and higher annual incidence of croup (Table).
Table. Traffic load, traffic-dependent pollutants and annual incidence of croup in children (Vinnytsya, Ukraine, 2000–2003)
Conclusions Croup in children is related to traffic load and traffic-dependent pollutants (SO2, NO2, particulate matter, CO).
Preview · Article · Mar 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background
The study aimed to define the frequencies of type 1 diabetes-associated gene polymorphisms and their associations with various diabetes-associated autoantibodies in Egyptian children.Methods
One hundred one children with type 1 diabetes and 160 healthy controls from the same region were studied for HLA-DQB1, -DQA1 and -DRB1 (DR4 subtypes) alleles, INS and PTPN22 gene polymorphisms (rs689 and rs2476601) and for diabetes-associated autoantibodies.ResultsMost diabetic children (77.2%) were positive for the HLA-(DR3)-DQA1*05-DQB1*02 (DR3-DQ2) haplotype compared to 26.2% of the controls (OR = 9.5; p < 0.001). HLA-DRB1*04:02-DQA1*03-DQB1*03:02 (DR4-DQ8) (26.7%, OR = 3.3; p < 0.001), DRB1*04:05-DQA1*03-DQB1*02 (DR4-DQ2) (23.8%, OR 5.2; p < 0.001) and DRB1*04:05-DQA1*03-DQB1*03:02 (DR4-DQ8) (8.9%, OR = 7.7; p = 0.007) were also significantly increased. HLA-(DR15)-DQB1*06:01, (DR13)-DQB1*06:03 and DRB1*04:03-DQA1*03-DQB1*03:02 were the most protective haplotypes with OR values from 0.04 to 0.06. Patients positive for DR3-DQ2 but negative for DR4 haplotypes had a high frequency of GAD antibodies (78%; p <0.001 vs. other genotypes) but only 26.6% of those with DR3-DQ2/DR4-DQ2 tested positive for GAD antibodies (p = 0.006 vs. other genotypes). Subjects with the DR4-DQ8 haplotype without DR3-DQ2 or DR4-DQ2 were more often positive for IA-2 and ZnT8 antibodies (55.5%; p =0.007 and 55.5%, p =0.01, respectively). The AA genotype of INS gene was more common in patients than controls (75.2% vs 59.5%, OR = 2.07; p = 0.018).Conclusions
Besides a strong HLA-DR3-DQ2 association a relatively high frequency of the DR4-DQ2 haplotype characterized the diabetic population. The low frequency of autoantibodies in children with HLA-DR4-DQ2 may indicate specific pathogenetic pathways associated with this haplotype. This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · Diabetes/Metabolism Research and Reviews
[Show abstract][Hide abstract] ABSTRACT: The rate of inflammation increases in elderly individuals, a phenomenon called inflammaging, and is associated with degenerative diseases. However, the causes of inflammaging and the origin of the associated inflammatory mediators have remained enigmatic. We show herein that there is a positive correlation between the number of sons born and C-reactive protein concentrations in 90-year-old women. This association is influenced by HLA genetics known to regulate the immune response against HY antigens.
Full-text · Article · Feb 2015 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: The consumption of foods rich in n-3 polyunsaturated fatty acids has been proposed to protect against childhood asthma. This study explores the association of food consumption (including cow's milk (CM) free diet) in early life, and the risk of atopic and non-atopic asthma.
Food intake of 182 children with asthma and 728 matched controls was measured using three-day food records, within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) -Nutrition Study cohort. The diagnoses of food allergies came both from the written questionnaire and from the registers of the Social Insurance Institution. Conditional logistic regression with generalized estimating equations framework was used in the analyses.
The diagnosis of cow's milk allergy (CMA) led to multiple dietary restrictions still evident at four years of age. Even after adjusting for CMA, higher consumption of CM products was inversely associated with the risk of atopic asthma and higher consumption of breast milk and oats inversely with the risk of non-atopic asthma. Early consumption of fish was associated with a decreased risk of all asthma.
Dietary intake in early life combined with atopy history has a clear impact on the risk of developing asthma. Our results indicate that CM restriction due to CMA significantly increases and mediates the association between food consumption and childhood asthma risk. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Feb 2015 · Pediatric Allergy and Immunology