Barbro Lernmark

Diabetes-associated HLA genotypes affect birthweight in the general population.

Aims/hypothesisThe aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight.MethodsHLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW).ResultsGenotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08–1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56–0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors.Conclusions/interpretationHLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

Congenital Cytomegalovirus Infection and Sensorineural Hearing Loss

In a prospective study still in progress, infants with congenital cytomegalovirus (CMV) infection were followed with audiological, ophthalmological, neurological, and psychological tests; 10,328 infants were investigated within a 5-year period (1977-1982) by virus isolation in urine within the first week of life. Fifty (0.5%) had a congenital CMV infection. In this group four children turned out to have total deafness and a fifth possibly a mild hearing disorder. In one case the deafness was associated with severe mental retardation and spastic tetraplegia. The mother of the child had a primary CMV infection in the first trimester. In one of the other cases of severe deafness it could be proven that the mother had had a secondary CMV infection and in further two cases, presumed secondary infections. Prospective serological tests of the mothers would not have revealed more than one of the high risk pregnancies. The value of vaccination against congenital CMV infection is questioned. Screening of newborn infants for congenital CMV infection is recommended in order to reveal infants at high risk for deafness and make an early habilitation possible.

Genetic and perinatal factors as risk for childhood type 1 diabetes

The mechanisms by which gestational infections, blood incompatibility, birth weight, mothers age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population‐based prospective studies. The possibility of identifying children at type 1 diabetes risk among first‐degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first‐degree relative with the disease. Population‐based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10 000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high‐risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase–related IA‐2 antigen (IA‐2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high‐risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright

Cord blood islet autoantibodies and seasonal association with the type 1 diabetes high-risk genotype

Objective:Human leukocyte antigen DQ (HLA-DQ) genetic factors and islet autoantibodies are strongly associated with type 1 diabetes (T1D) and are currently used to predict T1D. This study examined whether islet autoantibodies in the cord blood of newborns to nondiabetic mothers were associated with the (T1D) high-risk genotype HLA-DQ2/8, gestational infections or both.Study Design:Cord blood samples were taken from 33 683 newborns and used for HLA typing and analyses of islet autoantibodies. Parents completed questionnaires when the child was 2 months of age.Result:The prevalence of newborn islet autoantibodies consistently varied with season over 4 years (P<0.0001); lowest in first quarter (1.2%) and highest in third (2.4%). Cord blood islet autoantibodies were associated with HLA-DQ2/8 in the second (OR, 2.30; P=0.02), third (OR, 2.12; P=0.008) and fourth quarters (OR, 2.49; P=0.007), but not in the first (OR, 1.13). Reported gastroenteritis was additionally associated with islet autoantibodies in the third quarter (OR, 1.80, P=0.04).Conclusion:An association between HLA and islet autoimmunity may depend on environmental exposure during pregnancy. Follow-up of mothers and children will determine risk of T1D.

Differences in recruitment and early retention among ethnic minority participants in a large pediatric cohort: The TEDDY Study

OBJECTIVE The TEDDY Study is an international, multi-center prospective study designed to identify the environmental triggers of type 1 diabetes (T1D) in genetically at-risk children. This report investigates ethnic minority (EM) differences in patterns of enrollment and retention in the US centers. METHODS As of June 2009, 267,739 newborns had been screened at birth for high risk T1D genotypes. Data collected at the time of screening, enrollment and at the baseline visit were used. Descriptive and multiple-logistic regression analyses assessed differences between EM groups regarding exclusion, enrollment and early withdrawal. RESULTS Of the 10,975 eligible subjects, 6,912 (67%) were invited to participate. EM subjects were more likely to be excluded because of an inability to contact. Of those invited 3,265 (47%) enrolled by the age of 4.5 months. Adjusted analyses showed that except for those classified as other EM, the odds of enrolling were similar across groups. EM subjects had elevated early withdrawal rates. Adjusted models demonstrated that this was significantly more likely among Hispanic subjects. CONCLUSION Understanding patterns associated with EM participation in research extends our ability to make more accurate inferences and permits assessment of strategies that promote inclusion of EM to better address health disparities.

Enrollment Experiences in a Pediatric Longitudinal Observational Study: The Environmental Determinants of Diabetes in the Young (TEDDY) Study

OBJECTIVE Our objective was to identify characteristics of infants and their families who were enrolled, refused to enroll, or were excluded from The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHOD 16,435 infants screened at birth and identified as at increased genetic risk for type 1 diabetes (T1DM) were placed into one of three categories: enrolled, excluded, or refused to enroll. Enrollment, exclusion and refusal rates were compared across countries and between infants from the general population (GP) and infants with a first degree T1DM relative (FDR). A multivariate logistic model was used to identify factors associated with TEDDY enrollment. RESULTS TEDDY enrollment, exclusion, and refusal rates differed by country and by GP/FDR status but reasons for refusal to enroll were similar across countries and GP/FDR populations. Sweden had the highest enrollment rate, US had the highest exclusion rate, and Finland had the highest refusal rate. FDR infants were more likely to enroll than GP infants. Inability to re-contact the family was the most common reason for exclusion. Primary reasons for refusal to enroll included protocol factors (e.g. blood draws) or family factors (e.g., too busy). Study enrollment was associated with FDR status, European country of origin, older maternal age, a singleton birth, and having another child in TEDDY. CONCLUSIONS Findings highlight the importance of country specific estimates for enrollment targets in longitudinal pediatric studies and suggest that enrollment estimates should be lowered when the study involves the general population, painful procedures, or makes multiple demands on families.

The Environmental Determinants of Diabetes in the Young (TEDDY) Study: predictors of early study withdrawal among participants with no family history of type 1 diabetes

Johnson SB, Lee H‐S, Baxter J, Lernmark B, Roth R, Simell T for the TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) Study: predictors of early study withdrawal among participants with no family history of type 1 diabetes.

Cord blood islet autoantibodies are related to stress in the mother during pregnancy.

Abstract:  A 2‐month psychological questionnaire concerning pregnancy was answered by 20,920 nondiabetic mothers of singletons. Retrospective analysis showed increased levels of islet autoantibodies (IA) in 290 (1.4%) newborns. High IA levels in the childs cord blood correlated strongly with IA levels in the mother (GADA r= 0.91, P < 0.0001; IA‐2A r= 0.75, P= 0.0001). High IA levels were found in newborns whose mothers during pregnancy had been more worried than usual (P= 0.04), had worried that the child would be sick (P= 0.01) or not survive (P= 0.002), or had experienced serious life events, like “serious accident in the family” (P < 0.0001) or “experienced violence” (P= 0.02). Associations with increased worries by the mother remained in newborns with high type 1 diabetes mellitus (T1DM)‐human leukocyte antigen (HLA) risk, but not in non‐HLA risk children. The prospective follow‐up of these children will determine the importance of this early IA for postnatal islet autoimmunity, type 1 diabetes, or both.

The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.

Aims/hypothesisWe tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes.MethodsA total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain.ResultsThe frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51–0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51–0.88, p = 0.009).Conclusions/interpretationThe negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.

Islet cell autoantibody levels after the diagnosis of young adult diabetic patients

Aims  The aim was to determine the course of islet cell antibodies [glutamate decarboxylase (GADA), tyrosine phosphatase‐like islet antigen 2 (IA‐2A) and islet cell (ICA)] after the diagnosis of the diabetic patient.