In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

AIMS/HYPOTHESIS: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. METHODS: A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. RESULTS: Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk. CONCLUSIONS/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.

Care delivery and outcomes among Belgian children and adolescents with type 1 diabetes.

UNLABELLED: We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0-18 years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77 %) and had at least one parent of Belgian origin (78 %). Nearly all patients (≥95 %) underwent determination of HbA(1c) and BMI. Screening for retinopathy (55 %) and microalbuminuria (73 %) was less frequent, but rates increased with age and diabetes duration. Median HbA(1c) was 61 mmol/mol (7.7 %) [interquartile range 54-68 mmol/mol (7.1-8.4 %)] and increased with age and insulin dose. HbA(1c) was higher among patients on insulin pump therapy. Median HbA(1c) significantly differed between centres [from 56 mmol/mol (7.3 %) to 66 mmol/mol (8.2 %)]. Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA(1c) and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care. CONCLUSION: Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA(1c) remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.

Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Comparison of data from Antwerp with complete ascertainment with data from Belgium with 40% ascertainment. The Belgian Diabetes Registry.

OBJECTIVE: To compare the incidence rate of IDDM in the age-groups 0-14 and 15-39 years in Antwerp, Belgium, and to compare demographic, clinical, and biological data from Antwerp IDDM patients with 92% ascertainment with those from a larger Belgian patient group with 40% ascertainment. RESEARCH DESIGN AND METHODS: Incident cases of IDDM were reported by physicians of the Belgian Diabetes Registry and in Antwerp by several other sources. In Antwerp, completeness of ascertainment was calculated by the capture-recapture method. Demographic and clinical data were collected by questionnaire. Blood was sampled for HLA-DQ genotyping and, in new-inset patients, for autoantibodies. RESULTS: In Antwerp, the age- and sex-standardized IDDM incidence rates were similar in both age-groups (0-14 years: 11.8/100,000; 15-39 years: 8.9/100,000). The incidence rate decreased in girls above age 15 years (6.9/100,000; P = 0.003) but not in boys (11.0/100,000). Both in Antwerp and Belgium, IDDM was diagnosed more frequently in the 15-39 years age-group (60% of all cases) than under age 15 years, with a lower prevalence of acute symptoms, ketonuria, high-risk HLA-DQ genotype, and autoantibodies against insulin, islet cells, and IA-2, but with a higher prevalence of GAD65 autoantibodies. CONCLUSIONS: In Antwerp, the incidence rate of IDDM under age 15 years is intermediately high compared with the rates in other European regions. It is similar in the 15-39 years age-group, but with a marked male predominance. Demographic, clinical, and biological data show the same age-dependent heterogeneity as the data collected nationwide, with 40% ascertainment indicating the representativeness of the latter.

The age at diagnosis of type 1 diabetes continues to decrease in Belgian boys but not in girls: a 15-year survey.

BACKGROUND: The age at clinical onset of type 1 diabetes is decreasing. Preliminary Belgian data suggested that this anticipation occurred preferentially in boys. We investigated whether this gender-specific anticipation could be confirmed over a 15-year observation period. METHODS: In Antwerp, we studied incidence trends between 1989 and 2003 in 746 type 1 diabetic patients under age 40. For 2928 antibody-positive patients diagnosed nationwide during the same period, age at diagnosis was analysed according to gender and calendar year. RESULTS: In Antwerp, the incidence of type 1 diabetes under age 15 increased significantly with time from 10.9/100 000/year in 1989-1993 to 15.8/100 000/year in 1999-2003 (p = 0.008). The rising incidence in children was largely restricted to boys under age 10 where the incidence more than doubled during the 15-year period (6.8/100 000/year in 1989-1993 vs 17.2/100 000/year in 1999-2003; p < 0.001). Such an increase was not found in girls under age 10 (p = 0.54). This selective trend toward younger age at diagnosis in boys was confirmed in the larger group of Belgian patients where the median age at diagnosis decreased in boys-but not in girls-from 20 years in 1989-1993 to 15 years in 1999-2003 (p < 0.001). CONCLUSIONS: Over a 15-year observation period, a selective anticipation of clinical onset of type 1 diabetes was found in boys but not in girls. This suggests that an environmental factor may preferentially accelerate the sub-clinical disease process in young boys.

Seasonality in clinical onset of type 1 diabetes in belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence.

AIMS/HYPOTHESIS: Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes. METHODS: The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype. RESULTS: Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0-9 years: p=0.398; 10-19 years: p<0.001; 20-29 years: p=0.003; 30-39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.00 vs all others: n=927; p=0.031). CONCLUSIONS/INTERPRETATION: In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.