Twenty‐one years of prospective incidence of childhood type 1 diabetes in Hungary – the rising trend continues (or peaks and highlands?)

The aim of this study was to examine secular trends in the incidence of type 1 diabetes in children aged 0-14 yr in Hungary over the period 1989-2009. Newly diagnosed children with type 1 diabetes aged 0-14 yr in Hungary were prospectively registered from 1989 to 2009. Primary ascertainment of cases was by prospective registration using hospital notifications. Case ascertainment was over 96% complete using the capture-recapture method. Standardized incidence rates were calculated and secular trends estimated using Poisson regression analysis. In Hungary during 1989-2009 a total number of 3432 children were identified, giving a standardized incidence rate of 12.5 [95% confidence interval (CI) 12.1-12.9] per 100,000 person yr. The overall incidence rate has doubled from 7.7 (95% CI 6.4-9.15) per 100,000 per yr in 1989 to 18.2 (95% CI 15.7-20.9) per 100,000 per yr in 2009. A significant linear trend in incidence (p < 0.001) has been observed over time, with a mean annual increase of 4.4%. The increase in incidence was present in both genders and in all age groups, with the largest relative increase in the youngest age group (6.2%; p < 0.001). The incidence of type 1 diabetes in Hungarian children continues to increase, with the highest rate in the very young. Although it seems that transient periods of stabilization followed by increases in incidence are apparent, the long-term trend continues to be steadily upward. Incidence of childhood type 1 diabetes is a dynamic process, probably reflecting the changes of the environmental exposures and continued registration is necessary to recognize these trends.     

Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age,ketoacidosis, HLA status,and autoantibodies on residual beta‐cell function and glycemic control 12 months after diagnosis

HB Mortensen, PGF Swift, RW Holl, P Hougaard, L Hansen, H Bjoerndalen, CE de Beaufort, M Knip. Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age, ketoacidosis, HLA status, and autoantibodies on residual beta‐cell function and glycemic control 12 months after diagnosis. Objective: To identify predictors of residual beta‐cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D). Subjects and Methods: Clinical information and blood samples were collected from 275 children. HbA1c, antibodies, HLA typing and mixed meal‐stimulated C‐peptide levels 1, 6, and 12 months after diagnosis were analyzed centrally. Results: Mean age at diagnosis was 9.1 yr. DKA with standard bicarbonate <15 mmol/L was associated with significantly poorer residual beta‐cell function 1 (p = 0.004) and 12 months (p = 0.0003) after diagnosis. At 12 months, the decline in stimulated C‐peptide levels compared with the levels at 1 month was 69% in the youngest age group and 50% in patients 10 yr and above (p < 0.001). Stimulated C‐peptide at 12 months was predicted by younger age (p < 0.02) and bicarbonate levels at diagnosis (p = 0.005), and by stimulated C‐peptide (p < 0.0001), postmeal blood glucose (p = 0.0004), insulin antibodies (IA; p = 0.02) and glutamic acid decarboxylase antibodies (GADA; p = 0.0004) at 1 month. HbA1c at 12 months was predicted by HbA1c at diagnosis (p < 0.0001), GADA at 1 month (p = 0.01), and non‐white Caucasian ethnicity (p = 0.002). Conclusions: Younger age, ketoacidosis at diagnosis, and IA and GADA 1 month after diagnosis were the strongest explanatory factors for residual beta‐cell function at 12 months. Glycemic control at 12 months was influenced predominantly by ethnicity, HbA1c at diagnosis, and GADA at 1 month.     

Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA-identical siblings

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte-globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16.6, P = 0.001). Patients who received ATG and CsA had a significantly lower probability of failure-free survival than those who did not (69.7 +/- 6.2% vs. 87.9 +/- 8.0%, P = 0.044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen-identical siblings.     

CRYAB-650 C>G (rs2234702) affects susceptibility to Type 1 diabetes and IAA-positivity in Swedish population

BackgroundSingle nucleotide polymorphisms (SNPs) in the promoter region of CRYAB gene have been associated with in multiple sclerosis. CRYAB gene, which encodes alpha B-crystallin (a member of small heat shock protein), was reported as a potential autoimmune target. In this study we investigated whether SNPs in the promoter region of CRYAB gene were also important in the etiology of Type 1 diabetes (T1D).MethodsGenotyping of SNPs in the promoter region of CRYAB gene was performed in a Swedish cohort containing 444 T1D patients and 350 healthy controls. Three SNPs were included in this study: CRYAB-652 A>G (rs762550), -650 C>G (rs2234702) and -249 C>G (rs14133). Two SNPs (CRYAB-652 and -650) were not included in previous genome wide association studies.ResultsCRYAB-650 (rs2234702)*C allele was significantly more frequent in patients than in controls (OR = 1.48, Pc = 0.03). CRYAB-650*C allele was associated with IAA positivity (OR = 8.17, Pc < 0.0001) and IA–2A positivity (OR = 2.14, Pc = 0.005) in T1D patients. This association with IAA was amplified by high-risk HLA carrier state (OR = 10.6, P < 0.0001). No association was found between CRYAB-650 and other autoantibody positivity (GADA and ICA). CRYAB haplotypes were also associated with IAA and IA–2A positivity (highest OR = 2.07 and 2.11, respectively), these associations remain in high HLA-risk T1D patients.ConclusionsCRYAB-650 was associated with T1D in the Swedish cohort we studied. CRYAB-650*C allele might confers susceptibility to the development of T1D. CRYAB-650 was also associated with the development of IAA-positivity in T1D patients, especially in those carrying T1D high-risk HLA haplotypes.     

Systemic Levels of CCL2, CCL3, CCL4 and CXCL8 Differ According to Age,Time Period and Season among Children Newly Diagnosed with type 1 Diabetes and their Healthy Siblings

The mechanisms by which antigen‐specific T cells migrate to the islets of Langerhans in type 1 diabetes (T1D) are largely unknown. Chemokines attract immune cells to sites of inflammation. The aim was to elucidate the role of inflammatory chemokines in T1D at time of diagnosis. From a population‐based registry of children diagnosed with T1D from 1997 to 2005, we studied five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8). Four hundred and eighty‐two cases and 479 sibling frequencies matched on age and sample year distribution were included. Patients showed lower levels of CCL4 compared to siblings, but this result was not significant after correction for multiple testing. CCL2, CCL3, CCL4 and CXCL8 levels were highest in the most recent cohorts (P < 0.01) in both patients and siblings. A significant seasonal variation – for most of the chemokines – was demonstrated with the highest level during the summer period in both patients and siblings. In addition, there was a significant inverse relationship between CCL4 levels and age. When comparing patients and siblings, remarkably few differences were identified, but interestingly chemokine levels varied with age, season and period for the entire study population. Such variations should be taken into account when studying chemokines in paediatric populations.