Decreased cord-blood phospholipids in young age at onset type 1 diabetes.

Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. In this study metabolomics was used to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before eight years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before eight years of age and 76 healthy controls matched for HLA risk, gender and date of birth as well as mother's age and gestational age revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before four years of age. Reduced levels of triglycerides correlated to gestational age in both index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord blood total lysophosphatidylcholines in both index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute in early induction of islet autoimmunity

Determinants of maternal and fetal exposure and temporal trends of perfluorinated compounds.

In recent years, some perfluorinated compounds (PFCs) have been identified as potentially hazardous substances which are harmful to the environment and human health. According to limited data, PFC levels in humans could be influenced by several determinants. However, the findings are inconsistent. In the present study, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were measured in paired maternal and cord serum samples (N = 237) collected between 1978 and 2001 in Southern Sweden to study the relationship between these and to investigate several potential determinants of maternal and fetal exposure to PFCs. Time trends of PFCs in Swedish women were also evaluated. The study is a part of the Fetal Environment and Neurodevelopment Disorders in Epidemiological Research project. PFOS, PFOA, and PFNA levels (median) were higher in maternal serum (15, 2.1, and 0.24 ng/ml, respectively) than in cord serum (6.5, 1.7, and 0.20 ng/ml, respectively). PFC levels were among the highest in women originating from the Nordic countries and the lowest in women from the Middle East, North Africa, and sub-Saharan Africa. Multiparous women had lower serum PFOA levels (1.7 ng/ml) than primiparous women (2.4 ng/ml). Maternal age, body mass index, cotinine levels, and whether women carried male or female fetuses did not affect serum PFC concentrations. Umbilical cord serum PFC concentrations showed roughly similar patterns as the maternal except for the gestational age where PFC levels increased with advancing gestational age. PFOS levels increased during the study period in native Swedish women. In summary, PFOS levels tend to increase while PFOA and PFNA levels were unchanged between 1978 and 2001 in our study population. Our results demonstrate that maternal country of origin, parity, and gestational age might be associated with PFC exposure

Serological evaluation of possible exposure to Ljungan virus and related parechovirus in autoimmune (type 1) diabetes in children.

Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jämtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P < 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P < 0.001) and with insulin autoantibodies (P < 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P < 0.001) but only HPeV3-VP1_1-30-IgG (P < 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence. J. Med. Virol. © 2015 Wiley Periodicals, Inc

Comparison of Radioimmunoprecipitation With Luciferase Immunoprecipitation for Autoantibodies to GAD65 and IA-2β

OBJECTIVE - To compare the sensitivity and specificity of luciferase immunoprecipitation (LIPS) with radioimmunoprecipitation (RIP) for the measurement of autoantibodies to the type 1 diabetes autoantigens glutamic acid decarboxylase 65 (GAD65) and insulinoma-associated protein (IA)-2 beta. RESEARCH DESIGN AND METHODS - Sera from 49 type 1 diabetic patients and 100 nondiabetic control subjects from Diabetes Antibody Standardization Program 2007 were used to screen for autoantibodies to GAD65. An additional 200 type 1 diabetic patients and 200 nondiabetic control subjects were used to validate the GAD65 results and screen for autoantibodies to IA-2 beta. RESULTS - LIPS showed equal sensitivity and specificity to RIP for detecting autoantibodies to GAD65 and IA-2 beta. Receiver-operating characteristic analysis revealed that the detection of autoantibodies to GAD65 and IA-2 beta by LIPS and RIP were not statistically different. CONCLUSIONS - The LIPS assay does not require the use of radioisotopes or in vitro transcription/translation and is a practical alternative at the clinical level for the RIP assay

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D

Long-term Outcomes of Congenital Cytomegalovirus Infection in Sweden and the United Kingdom

Background. Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. Methods. Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. Results. One hundred seventy-six congenitally infected infants were identified among &gt;50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. Conclusions. Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease

Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA.

BACKGROUND: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. AIM: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). RESULTS: Bioactive IGF increased with age in healthy pre-pubertal children (n=94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, p2SD (mean IGF-I 2.8 SDS), whereas only 15% (n=15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r=0.29, p=0.005), in contrast to IGF-I (SDS) (r=0.17, p=0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r=-0.22, p=0.02). CONCLUSION: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment

Genetic markers of insulin sensitivity and insulin secretion are associated with spontaneous postnatal growth and response to growth hormone treatment in short SGA children: the North European SGA Study (NESGAS).

PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele; 95% CI, 0.00-0.32; P = .03). The association with first-year height velocity was independent of reported predictors of response to GH therapy (adjusted P = .04). The insulin secretion allele score (GS-InSec) was positively associated with spontaneous postnatal height gain (B: 0.15; 95% CI, 0.01-0.30; P = .03) and disposition index both before (B: 0.02; 95% CI, 0.00-0.04; P = .04) and after 1 year of GH therapy (B: 0.03; 95% CI, 0.01-0.05; P = .002), but not with growth and IGF-1 responses to GH therapy. Neither of the allele scores was associated with size at birth. CONCLUSION: Genetic allele scores indicative of insulin sensitivity and insulin secretion were associated with spontaneous postnatal growth and responses to GH therapy in short SGA children. Further pharmacogenetic studies may support the rationale for adjuvant therapies by informing the mechanisms of treatment response.This study was funded by a research grant from The Danish Council for Independent Research/ Medical Sciences and a research grant from Novo Nordisk A/S.This is the accepted manuscript. The final version is available at http://dx.doi.org/10.1210/jc.2014-3469

Maternal Enterovirus Infection during Pregnancy as a Risk Factor in Offspring Diagnosed with Type 1 Diabetes between 15 and 30 Years of Age

Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offspring's risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22–17.6), as compared to boys of IgM-negative mothers (P < .025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.Juvenile Diabetes Research Foundation International (2-2000-570) and (1-2001-873The Swedish Research CouncilSvenska Diabetes FondenBarndiabetes FondenNovo Nordisk FoundationMagnus Bergvalls FoundationNeuropromise (LSHM-CT-2005-018637)NIH grant DK-17047Swedish Brain Power initiativeGun and Bertil Stohne’s Foundation,Foundation for Old ServantsAlzheimer FoundationLIONS Foundation for Research of Age Related DisordersAFA foundationSöderberg FoundationKnut and Alice Wallenbergs FoundationManuscrip