Kristian Lynch

Common variants in MODY genes increase the risk of gestational diabetes mellitus.

Aims/hypothesisImpaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM.Subjects and methodsWe genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women).ResultsThe A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM.Conclusions/interpretationThe −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.

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 33u2009683 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.

Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes

Aims/hypothesisHigh birthweight and increased childhood growth are risk factors for type 1 diabetes. Relative birthweight is associated with HLA genotypes that confer a high risk of diabetes. Our aims were to test whether young children prior to clinical onset of type 1 diabetes have increased: (1) birthweight or birth length standard deviation scores (SDS); (2) height development SDS; or (3) BMI SDS during first 18xa0months of life and whether these parameters are related to HLA genotypes or mid-parental height (MPH).MethodsBirthweight, birth length, weight and height were obtained from 58 type 1 diabetes children and 155 controls matched for HLA or not in the Diabetes Prediction in Skåne study.ResultsBirth length SDS corrected for MPH was increased in children developing diabetes compared with all (pu2009<u20090.048) and with non-HLA- (pu2009<u20090.050) but not with HLA-matched controls. Children developing diabetes had increased height gain at 0 to 18xa0months of age (pu2009<u20090.005). Diabetic children were significantly taller from 6 to 18xa0months of age when correcting for MPH compared with non-HLA-matched as well as HLA-matched controls, but BMI was not increased.Conclusions/interpretationBirth length SDS was associated with diabetes risk HLA. When corrected for MPH, children developing diabetes were taller at birth than non-HLA- but not taller than HLA-matched controls. Diabetic children had increased MPH-corrected height up to 18xa0months of age compared with both HLA- and non-HLA-matched controls. High-risk HLA affects prenatal growth, but other factors may explain the increased postnatal linear growth in children developing diabetes.

Evidence for immunological priming and increased frequency of CD4(+) CD25(+) cord blood T cells in children born to mothers with type 1 diabetes.

Maternal transmission of islet autoantibodies to children born to mothers with type 1 diabetes (T1D) has been shown to protect from autoantibodies and diabetes development later in life. However, the factors conferring disease protection are poorly understood. The aim of this study was to evaluate comparatively proinflammatory cytokines, autoantibodies and lymphocyte subsets in cord blood (CB) of children born to mothers with either T1D (nu2003=u200313), gestational diabetes (GDM) (nu2003=u200332) or healthy mothers (nu2003=u200381) in relation to transplacental passage of autoantibodies. The results are consistent with early priming of the fetal immune system only in children born to mothers with T1D. Levels of interleukin (IL)‐1β (Pu2003=u20030·022), tumour necrosis factor (TNF)‐α (Pu2003=u20030·002) and IL‐8 (Pu2003=u20030·0012), as well as the frequency of CD4+u2003CD25+ T cells (Pu2003<u20030·01) were significantly increased, and the increased levels correlated positively with anti‐GAD65 autoantibody (GADA) levels. Moreover, CD4+u2003CD25+ T cells of children born to T1D mothers exhibited a more pronounced memory phenotype with increased CCR4 expression and down‐regulation of CD62L. These data suggest that early activation of the fetal immune system as a consequence of maternal autoimmunity and transplacental passage of GADA may influence the generation and expansion of fetal regulatory T cells. This might induce an early antigen‐specific immunological tolerance that could protect against T1D later in life.

Number of islet autoantibodies present in newly diagnosed type 1 diabetes children born to non‐diabetic mothers is affected by islet autoantibodies present at birth

Objective:u2002 Cord blood islet autoantibodies in children born to mothers with type 1 diabetes may be associated with a reduced risk of islet autoimmunity and diabetes. The aim of this study was to investigate in children with type 1 diabetes but born to non‐diabetic mothers whether islet autoantibodies at birth affected their presence at diagnosis.

Using radioligand-binding assays to measure tissue transglutaminase autoantibodies in young children

Aim: To measure autoantibodies against tissue transglutaminase (tTG) in young children prospectively screened for coeliac disease (CD). Methods: In total, 652 children aged 2.9 (2.5–4.2) y were analysed for IgA‐tTG and IgG‐tTG with radioligand‐binding assays and IgA endomysial antibodies (EMA) by indirect immunofluorescence. Antibody‐positive children were retested after 1.2 (range 0.2–1.9) y. Intestinal biopsy was performed on children with persistently high antibody levels. Results: In total, 3.2% (95% CI: 1.9–4.6%) of the 652 children were positive for at least one antibody at baseline: 2.5% (95% CI: 1.3–3.7%) for IgA‐tTG, 1.7% (95% CI: 0.7–2.7%) for IgG‐tTG and 2.9% (95% CI: 1.6–4.2%) for IgA‐EMA, respectively. Ten children were positive for all three antibodies, five for both IgA‐tTG and EMA, four for EMA only, one for IgA‐tTG and another for IgG‐tTG. IgA‐EMA titres correlated with IgA‐tTG levels (r= 0.73, p= 0.0003). At follow‐up, seven of 20 children remained positive for all three antibodies, three for IgA‐tTG only, one for both IgA‐tTG and EMA, one for IgA‐tTG and IgG‐tTG, and the remaining child refused further participation. Three biopsies showed villous atrophy, two increased intraepithelial lymphocytes and two normal findings. Biopsy was not performed in four children with low or declining tTG antibody levels at follow‐up and in one child who declined. CD was evident in 0.5% (95% CI: 0.0–1.0%) (3/652).

Temporal Variation of Ljungan Virus Antibody Levels in Relation to Islet Autoantibodies and Possible Correlation to Childhood Type 1 Diabetes

Viral infection may trigger islet autoimmunity, type 1diabetes (T1D), or both. Fluctuating population density of bank voles as a putative reservoir of Ljungan virus has been claimed to be associated with variations in T1D incidence rate (IR). We tested the hypothesis that Ljungan virus antibodies reflecting prior exposure(s) to the virus may be associated with islet autoimmunity, childhood diabetes or both. Incident, 0-18y, T1D patients (n = 63) were studied along with age and sample time matched controls (n = 126). The younger children (< 9 years) tended to have a higher incidence rate during winter (IR = 67.6, 95%CI 41.9-103.5) compared to summer (IR = 33.6, 95%CI 15.3-63.9) months. The proportion of children with high level antibodies against Ljungan virus (LVAb) were both younger compared to the rest of the children (p < 0.002) and correlated with half yearly T1D IR (r = 0.78, p = 0.005). High level LVAb fluctuating with season and correlating with T1D IR indicates that past exposure to Ljungan virus may be associated with T1D.

Islet Cell Autoantigens

Type 1 diabetes (T1D) appears after autoimmune processes have eradicated a large majority of the pancreatic islet β cells. Although patients may also have other organ-specific autoimmune diseases such as thyroiditis or celiac disease (CD), most T1D patients suffer from life-long insulin dependence because only the β cells have been eradicated. The genetic etiology is strongly associated with certain HLA-DQ class II heterodimers, which in part may explain the cell-specific loss as these proteins control antigen processing and presentation. Other etiologies include environmental factors such as virus and environmental or dietary toxins. The pathogenesis is closely associated with a number of autoimmune abnormalities, among them are autoantibodies and T cells to specific autoantigens. Autoantibody assays, standardized in international efforts, are used to identify autoantibodies against the islet autoantigens insulin, GAD65 and islet antigen-2 (IA-2). The presence of autoantibodies to these autoantigens predicts T1D. Other β-cell autoantigens have been reported but have failed confirmation especially because such antigens have failed to predict disease. The possible pathogenic importance of minor candidate autoantigens is typically not pursued. Reproducible and standardized T-cell tests of either CD4- or CD8-positive T cells are yet to be developed. Immunomodulating therapies with insulin and GAD65 are in progress, and preliminary data indicate that it may be possible to alter the T1D pathogenic process.