rs11203203 is associated with type 1 diabetes risk in population pre-screened for high-risk HLA-DR,DQ genotypes.

OBJECTIVE: To evaluate UBASH3A (rs11203203) as a predictor of persistent islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) followed prospectively for development of persistent IA (autoantibodies to insulin, GAD65, IA-2, or ZnT8 on at least two consecutive exams) and diabetes 1715 non-Hispanic white children at increased genetic risk for T1D. The DAISY participants were genotyped for rs11202203 (UBASH3A). RESULTS: UBASH3A allele A was associated with development of IA [hazard ratio (HR) = 1.46, 95%CI = 1.11-1.91, p = 0.007] and diabetes (HR = 1.84, 95%CI = 1.28-2.64, p = 0.001), controlling for presence of HLA-DR3/4,DQB1*0302 and having a first-degree relative (FDR) with T1D. The UBASH3A AA genotype conferred higher risk of persistent IA (12.7%) and diabetes (6.1%) by age 10 than for AG (7.7 and 3.1%, respectively) or GG (5.3 and 2.0%) genotype (p = 0.009 for IA, p = 0.0004 for diabetes). Among children with no family history of T1D, but HLA-DR3/4,DQB1*0302 and UBASH3A AA genotype, 35.9% developed IA and 50.6% developed diabetes by age 15. CONCLUSIONS: UBASH3A appears to be an independent predictor of IA and T1D in children, including those free of family history of T1D but carrying the HLA-DR3/4,DQB1*0302 genotype. If confirmed, UBASH3A may prove useful in T1D risk prediction and pre-screening of the general population children for clinical trials.

Dietary glycemic index, development of islet autoimmunity, and subsequent progression to type 1 diabetes in young children.

CONTEXT: Dietary factors may trigger or exacerbate the autoimmune disease process. OBJECTIVE: Our objective was to examine dietary glycemic index (GI) and glycemic load (GL) for association with islet autoimmunity (IA) development, and progression from IA to type 1 diabetes. DESIGN: The Diabetes Autoimmunity Study in the Young follows children at increased genetic type 1 diabetes risk. Diet is collected prospectively via a parent-reported food frequency questionnaire. SETTING: This was an observational study of children in the Denver area. PATIENTS: A total of 1776 Diabetes Autoimmunity Study in the Young children younger than 11.5 yr was included in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: IA, defined as the presence of autoantibodies to insulin, glutamic acid decarboxylase, or protein tyrosine phosphatase at two consecutive visits, or the presence of autoantibodies at one visit and diabetic on the next consecutive visit was determined. Type 1 diabetes was diagnosed by a physician. A total of 89 subjects developed IA, and 17 subsequently developed type 1 diabetes during follow-up. Our hypothesis was formulated after data collection. RESULTS: GI and GL were not associated with IA development. More rapid progression to type 1 diabetes in children with IA was associated with higher dietary GI (hazard ratio: 2.20; 95% confidence interval: 1.17-4.15) and marginally associated with GL (hazard ratio: 1.59; 95% confidence interval: 0.96-2.64) at the first IA-positive visit. CONCLUSIONS: Higher dietary GI and GL are not associated with IA development, but higher GI is associated with more rapid progression to type 1 diabetes in children with IA, perhaps due to increased demand on the beta-cell to release insulin. Further study is needed to confirm this finding and identify the underlying biological mechanism.

Maternal diet during pregnancy and islet autoimmunity in offspring.

BACKGROUND: Recent studies on the etiology of type 1 diabetes mellitus (T1DM) suggest that the components of the infant diet are associated with islet autoimmunity (IA), a precursor of T1DM. The role of prenatal nutritional exposures has not been thoroughly investigated. METHODS: The Diabetes Autoimmunity Study in the Young has enrolled newborns from 1993 to 2004 at increased risk for T1DM based on human leukocyte antigen (HLA) genotype and family history of T1DM. The child is tested for islet autoantibodies at 9 and 15 months, 2 yr, and annually thereafter. We conducted a cohort study of 642 subjects for whom a Willett food frequency questionnaire for the mother's third trimester diet was completed. A case is defined as a subject who tests positive for islet autoantibodies at two consecutive blood draws and is still positive (or diabetic) at last follow-up (n = 27). Maternal consumption frequencies of potatoes, other root vegetables, gluten-containing foods, non-gluten cereal grains, cow's milk and cow's milk products, fruits, vegetables, meat and poultry, and fish were analyzed in a survival analysis. RESULTS: Adjusting for breast-feeding duration, age at first cereal introduction, ethnicity, HLA genotype, family history of T1DM, and total caloric intake, higher maternal intake of potatoes (hazard ratio for one standard deviation difference: 0.49, 95% confidence interval: 0.28-0.86) was associated with a delayed time to IA onset. No other food groups ingested during pregnancy were associated with IA in the child. CONCLUSIONS: The composition of the maternal diet during pregnancy may play a role in the offspring's risk of development of IA and potentially T1DM.

Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes.

CONTEXT: Cod liver oil supplements in infancy have been associated with a decreased risk of type 1 diabetes mellitus in a retrospective study. OBJECTIVE: To examine whether intakes of omega-3 and omega-6 fatty acids are associated with the development of islet autoimmunity (IA) in children. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal, observational study, the Diabetes Autoimmunity Study in the Young (DAISY), conducted in Denver, Colorado, between January 1994 and November 2006, of 1770 children at increased risk for type 1 diabetes, defined as either possession of a high diabetes risk HLA genotype or having a sibling or parent with type 1 diabetes. The mean age at follow-up was 6.2 years. Islet autoimmunity was assessed in association with reported dietary intake of polyunsaturated fatty acids starting at age 1 year. A case-cohort study (N = 244) was also conducted in which risk of IA by polyunsaturated fatty acid content of erythrocyte membranes (as a percentage of total lipids) was examined. MAIN OUTCOME MEASURE: Risk of IA, defined as being positive for insulin, glutamic acid decarboxylase, or insulinoma-associated antigen-2 autoantibodies on 2 consecutive visits and still autoantibody positive or having diabetes at last follow-up visit. RESULTS: Fifty-eight children developed IA. Adjusting for HLA genotype, family history of type 1 diabetes, caloric intake, and omega-6 fatty acid intake, omega-3 fatty acid intake was inversely associated with risk of IA (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21-0.96; P = .04). The association was strengthened when the definition of the outcome was limited to those positive for 2 or more autoantibodies (HR, 0.23; 95% CI, 0.09-0.58; P = .002). In the case-cohort study, omega-3 fatty acid content of erythrocyte membranes was also inversely associated with IA risk (HR, 0.63; 95% CI, 0.41-0.96; P = .03). CONCLUSION: Dietary intake of omega-3 fatty acids is associated with reduced risk of IA in children at increased genetic risk for type 1 diabetes.

Secondary attack rate of type 1 diabetes in Colorado families.

OBJECTIVE: Families of children diagnosed with type 1 diabetes require counseling concerning type 1 diabetes risk in nondiabetic siblings and parents. No U.S. population-specific life-table risk estimates are currently available for parents, and those for siblings (2-6% by age 20 years) are based on family studies completed before 1987. RESEARCH DESIGN AND METHODS: We analyzed family histories of 1,586 patients in Colorado with type 1 diabetes (83% non-Hispanic white, 10% Hispanic, and 7% other) diagnosed before 16 years of age and interviewed during 1999-2002. Families of probands with type 2, undetermined, or secondary diabetes (n = 53) or those with incomplete data (n = 137) were excluded. The median age at onset of the proband was 7.1 years and the median diabetes duration 3.5 years. Cumulative risk estimates were calculated using survival analysis for 2,081 full siblings and 3,016 biological parents. RESULTS: In siblings, the overall risk of type 1 diabetes by age 20 years was 4.4%, but it was significantly (P < 0.0001) higher in siblings of probands diagnosed under age 7 years than in those diagnosed later. In parents, the overall risk by age 40 years was 2.6% and higher in fathers (3.6%) than in mothers (1.7%) of probands (P < 0.001). Similar to siblings, the risk was also higher (P = 0.006) in parents of probands diagnosed <7 years of age than in those diagnosed later. CONCLUSIONS: Current risks of type 1 diabetes in Colorado siblings and parents of type 1 diabetic probands are higher than in the 1982 Pittsburgh study but similar to contemporary European rates. Recurrence risk of type 1 diabetes is significantly higher in first-degree relatives of probands diagnosed at a young age.

Elevated C-reactive protein levels in the development of type 1 diabetes.

Elevated C-reactive protein (CRP) levels have previously been described before the onset of type 2 diabetes and gestational diabetes. We hypothesized that inflammation, as reflected by elevated CRP levels, can help predict development of islet autoimmunity or type 1 diabetes. Children at risk for type 1 diabetes and followed in the Diabetes Autoimmunity Study of the Young (DAISY) had blood samples drawn and frozen serum saved at various intervals after birth. CRP was measured using a high-sensitivity sandwich enzyme immunoassay. Islet autoantibodies (IAs) were measured using biochemical immunoassays. Elevations in CRP concentrations were significantly more frequent (P < 0.01) in children who later developed type 1 diabetes (8 of 16 children) than in children negative for IAs at their last testing (3 of 26). Children with one or more positive IA were more likely to have elevated CRP concentrations (15 of 36) than IA-negative children (3 of 26; P < 0.01). The finding of elevated CRP levels in infants and young children before the onset of type 1 diabetes adds to the evidence that the disease is an immunoinflammatory disorder. The elevated CRP levels may provide an additional marker for risk of progression to type 1 diabetes.

Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.

CONTEXT: While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease. OBJECTIVE: To examine whether the timing of gluten exposure in the infant diet was associated with the development of celiac disease autoimmunity (CDA). DESIGN, SETTING, AND PATIENTS: Prospective observational study conducted in Denver, Colo, from 1994-2004 of 1560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes. The mean follow-up was 4.8 years. MAIN OUTCOME MEASURE: Risk of CDA defined as being positive for tissue transglutaminase (tTG) autoantibody on 2 or more consecutive visits or being positive for tTG once and having a positive small bowel biopsy for celiac disease, by timing of introduction of gluten-containing foods into the diet. RESULTS: Fifty-one children developed CDA. Findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6%] CDA positive vs 40 [3%] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23%] CDA positive vs 574 [38%] CDA negative) (hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57). Children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs 895 [59%] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months (HR, 1.87; 95% CI, 0.97-3.60). After restricting our case group to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first 3 months (3 [12%] CDA positive vs 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs 912 [59%] CDA negative) significantly increased risk of CDA compared with exposure at 4 to 6 months (3 [12%] CDA positive vs 583 [38%] CDA negative) (HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively). CONCLUSION: Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease.

Symptoms of common maternal infections in pregnancy and risk of islet autoimmunity in early childhood.

OBJECTIVE: The aim of this study was to test whether symptoms of maternal infections during pregnancy and indicators of postnatal infections predict development of islet autoimmunity in children at genetically increased risk of type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 871 children with type 1 diabetes-associated HLA genotypes born in Denver, Colorado, and 391 siblings or offspring of individuals with type 1 diabetes referred from clinics in the Denver metropolitan area were enrolled soon after birth and seen in the clinic at age

Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY).

OBJECTIVE: To determine whether the presence of islet autoantibodies in the umbilical cord blood is predictive of subsequent development of islet autoimmunity. RESEARCH DESIGN AND METHODS: Cord blood sera from 1,118 subjects from the Diabetes Autoimmunity Study in the Young (DAISY) cohort, as well as their venous blood samples taken at follow-up clinic visits, were tested for GAD65 autoantibodies (GAAs), insulin autoantibodies (IAAs), and IA-2 autoantibodies (IA-2As). Venous blood samples taken from mothers of cord blood autoantibody-positive children were analyzed for the same autoantibodies. RESULTS: At least one of three islet autoantibodies was present in 42 (3.7%) of the cord blood samples tested. The presence of cord blood autoantibodies did not predict the subsequent development of islet autoimmunity (adjusted hazard ratio = 0.73 [0.09, 5.88]). Discordance between cord blood and corresponding maternal autoantibodies was seen in 3 of 36 infants. A strong correlation between levels of autoantibody in cord blood and maternal circulation was found for GAA (r(2) = 0.93, P < 0.001) and IAA (r(2) = 0.89, P < 0.001) but not IA-2A (r(2) = 0.05, P = 0.19). Cord blood autoantibodies in all but one subject disappeared by 9 months of age. CONCLUSIONS: The presence of cord blood autoantibodies is not predictive of subsequent development of islet autoimmunity. The majority of cord blood autoantibodies appear to result from maternal transmission.

Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up.

OBJECTIVE: The objective of this study was to determine whether earlier diagnosis of diabetes in prospectively followed autoantibody-positive children lowered onset morbidity and improved the clinical course after diagnosis. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows genetically at-risk children for the development of diabetes. Increased genetic risk is identified by family history of type 1 diabetes or expression of diabetes-associated HLA genotypes. Of the 2,140 prospectively followed children, 112 have developed islet autoantibodies and 30 have progressed to diabetes. Diabetes onset characteristics and early clinical course of these 30 children followed to diabetes were compared with those of 101 age- and sex-matched children concurrently diagnosed with diabetes in the community. RESULTS: Pre-diabetic children followed to diabetes were less often hospitalized than the community cases (3.3 vs. 44%; P < 0.0001). They had a lower mean HbA(1c) at onset (7.2 vs. 10.9%; P < 0.0001) and 1 month after diagnosis (6.9 vs. 8.6%; P < 0.0001) but not after 6 months of diabetes. The mean insulin dose was lower in the DAISY group at 1 (0.30 vs. 0.51 U. kg(-1). day(-1); P = 0.003), 6 (0.37 vs. 0.58; P = 0.001), and 12 months (0.57 vs. 0.72; P = 0.03). There was no difference in growth parameters between the two groups. Comparisons limited to children with a family history of type 1 diabetes in both groups showed a similar pattern. CONCLUSIONS: Childhood type 1 diabetes diagnosed through a screening and follow-up program has a less severe onset and a milder clinical course in the first year after diagnosis.

Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY).

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.

Timing of initial cereal exposure in infancy and risk of islet autoimmunity.

CONTEXT: Dietary exposures in infancy have been implicated, albeit inconsistently, in the etiology of type 1 diabetes mellitus (DM). OBJECTIVE: To examine the association between cereal exposures in the infant diet and appearance of islet autoimmunity (IA). DESIGN: Birth cohort study conducted from 1994 to 2002 with a mean follow-up of 4 years. SETTING: Newborn screening for HLA was done at St Joseph's Hospital in Denver, Colo. First-degree relatives of type 1 DM individuals were recruited from the Denver metropolitan area. PARTICIPANTS: We enrolled 1183 children at increased type 1 DM risk, defined as either HLA genotype or having a first-degree relative with type 1 DM, at birth and followed them prospectively. We obtained exposure and outcome measures for 76% of enrolled children. Participants had variable lengths of follow-up (9 months to 9 years). MAIN OUTCOME MEASURES: Blood draws for the detection of insulin autoantibody, glutamic acid decarboxylase autoantibody, or IA-2 autoantibody were performed at 9, 15, and 24 months and annually thereafter. Children with IA (n = 34) were defined as those testing positive for at least 1 of the autoantibodies on 2 or more consecutive visits and who tested positive or had diabetes on their most recent visit. RESULTS: Children initially exposed to cereals between ages 0 and 3 months (hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.0-9.35) and those who were exposed at 7 months or older (HR, 5.36; 95% CI, 2.08-13.8) had increased hazard of IA compared with those who were exposed during the fourth through sixth month, after adjustment for HLA genotype, family history of type 1 DM, ethnicity, and maternal age. In children who were positive for the HLA-DRB1*03/04,DQB8 genotype, adjusted HRs were 5.55 (95% CI, 1.92-16.03) and 12.53 (95% CI, 3.19-49.23) for initial cereal exposure between ages 0 to 3 months and at 7 months or older, respectively. CONCLUSION: There may be a window of exposure to cereals in infancy outside which initial exposure increases IA risk in susceptible children.

Infant exposures and development of type 1 diabetes mellitus: The Diabetes Autoimmunity Study in the Young (DAISY).

IMPORTANCE: The incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide, with the most rapid increase among children younger than 5 years of age. OBJECTIVE: To examine the associations between perinatal and infant exposures, especially early infant diet, and the development of T1DM. DESIGN: The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal, observational study. SETTING: Newborn screening for human leukocyte antigen (HLA) was done at St. Joseph's Hospital in Denver, Colorado. First-degree relatives of individuals with T1DM were recruited from the Denver metropolitan area. PARTICIPANTS: A total of 1835 children at increased genetic risk for T1DM followed up from birth with complete prospective assessment of infant diet. Fifty-three children developed T1DM. EXPOSURES: Early (<4 months of age) and late (≥6 months of age) first exposure to solid foods compared with first exposures at 4 to 5 months of age (referent). MAIN OUTCOME AND MEASURE: Risk for T1DM diagnosed by a physician. RESULTS: Both early and late first exposure to any solid food predicted development of T1DM (hazard ratio [HR], 1.91; 95% CI, 1.04-3.51, and HR, 3.02; 95% CI, 1.26-7.24, respectively), adjusting for the HLA-DR genotype, first-degree relative with T1DM, maternal education, and delivery type. Specifically, early exposure to fruit and late exposure to rice/oat predicted T1DM (HR, 2.23; 95% CI, 1.14-4.39, and HR, 2.88; 95% CI, 1.36-6.11, respectively), while breastfeeding at the time of introduction to wheat/barley conferred protection (HR, 0.47; 95% CI, 0.26-0.86). Complicated vaginal delivery was also a predictor of T1DM (HR, 1.93; 95% CI, 1.03-3.61). CONCLUSIONS AND RELEVANCE: These results suggest the safest age to introduce solid foods in children at increased genetic risk for T1DM is between 4 and 5 months of age. Breastfeeding while introducing new foods may reduce T1DM risk.

Extrapancreatic autoantibody profiles in type I diabetes.

Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing ß-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-ß. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-ß (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.

Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young.

OBJECTIVE: We evaluated predictors of progression to diabetes in children with high-risk HLA genotypes and persistent islet autoantibodies. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) followed 2,542 children with autoantibodies measured to GAD, IA-2, and insulin. RESULTS: Persistent islet autoantibodies developed in 169 subjects, and 55 of those progressed to diabetes. Children expressing three autoantibodies showed a linear progression to diabetes with 74% cumulative incidence by the 10-year follow-up compared with 70% with two antibodies and 15% with one antibody (P < 0.0001). Both age of appearance of first autoantibody and insulin autoantibody (IAA) levels, but not GAD or IA-2 autoantibodies, were major determinants of the age of diabetes diagnosis (r = 0.79, P < 0.0001). CONCLUSIONS: In the DAISY cohort, 89% of children who progressed to diabetes expressed two or more autoantibodies. Age of diagnosis of diabetes is strongly correlated with age of appearance of first autoantibody and IAA levels.

Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY).

OBJECTIVE: To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies. RESEARCH DESIGN AND METHODS: Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3-6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5' noncoding region, detecting essentially all enterovirus serotypes. RESULTS: Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found. CONCLUSIONS: This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.

Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes?

OBJECTIVE: Specific alleles of non-HLA genes INS, CTLA-4, and PTPN22 have been associated with type 1 diabetes. We examined whether some of these alleles influence development of islet autoimmunity or progression from persistent islet autoimmunity to type 1 diabetes in children with high-risk HLA-DR,DQ genotypes. RESEARCH DESIGN AND METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,449 young children carrying HLA-DR,DQ genotypes associated with type 1 diabetes. Of those, 112 have developed islet autoimmunity (persistent autoantibodies to insulin, GAD65, and/or IA-2), and 47 of these have progressed to type 1 diabetes. The influence of polymorphisms of INS(-23Hph1), CTLA-4(T17A), and PTPN22(R620W) on development of persistent islet autoimmunity and progression to type 1 diabetes was evaluated by parametric models and by survival analyses. RESULTS: PTPN22(R620W) allele T was associated with development of persistent islet autoimmunity (hazard ratio 1.83 [95% CI 1.27-2.63]) controlling for ethnicity, presence of HLA-DR3/4,DQB1*0302, and having a first-degree relative with type 1 diabetes. Survival analyses showed a significantly (P = 0.002) higher risk of persistent islet autoimmunity by age 10 years for the TT genotype (27.3%) than for the CT or CC genotype (7.9 and 5.3%, respectively). Cumulative risk of persistent islet autoimmunity was slightly higher (P = 0.02) for the INS(-23Hph1) AA genotype (7.8%) than for the AT or TT genotype (4.2 and 6.4% risk by age 10 years, respectively). CONCLUSIONS: Whereas the HLA-DR3/4,DQB1*0302 genotype had a dramatic influence on both development of islet autoimmunity and progression to type 1 diabetes, the PTPN22(R620W) T allele significantly influences progression to persistent islet autoimmunity in the DAISY cohort.

HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population.

OBJECTIVE: A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as >85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403. RESEARCH DESIGN AND METHODS: We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequence-specific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes. RESULTS: By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is approximately 55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P = 0.02) with either protective allele, and the risk is 20 vs. 2% (P = 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies. CONCLUSIONS: The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.

Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY).

OBJECTIVE: The aim of this study was to assess the utility of hemoglobin A1c (HbA1c) measurements in the early detection of clinical type 1 diabetes during prospective follow-up of children with islet autoimmunity. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) has followed for development of islet autoimmunity and diabetes general population newborns carrying human leukocyte antigen (HLA) genotypes conferring risk for type 1 diabetes and young siblings or offspring of people with type 1 diabetes. Testing for autoantibodies was performed at least once in 2234 and twice or more in 1887 children. Among the latter, 100 children tested positive on at least two consecutive visits. To date, 92 children have developed persistent islet autoantibodies to glutamic acid decarboxylase 65 (GAD65), insulin, or insulinoma associated antigen-2 (IA-2) and had at least two subsequent clinic visits. These children had study visits with point-of-care testing for HbA1c and random glucose every 3-6 months and those with random plasma glucose above 11.1 mmol/L or HbA1c above 6.3% were evaluated by a pediatric endocrinologist for clinical diabetes. RESULTS: During a mean follow-up of 3.4 yr from onset of autoimmunity, 28 children developed type 1 diabetes, at mean age of 6.5 yr. Mean prediagnostic HbA1c was 5.1% [standard deviation (SD) = 0.4%]. In a Cox regression model accounting for changes in values in individuals over time, increase in HbA1c predicted increased risk of progression to type 1 diabetes, hazard ratio = 4.8 (95% confidence interval 3.0-7.7) for each SD of 0.4%, independent of random glucose and number of autoantibodies. Increase in random plasma glucose levels only marginally predicted risk of progression (hazard ratio = 1.4, 95% confidence interval 1.02-1.8, per SD of 1.1 mmol/L). CONCLUSIONS: Normal but increasing Hb1Ac may be useful in early detection of type 1 diabetes, whereas random plasma glucose levels were less predictive.

Association of the PTPN22/LYP gene with type 1 diabetes.

OBJECTIVES: The goal of this study was to verify the association between type 1 diabetes (T1D) and the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene in non-Hispanic whites (NHWs) and Hispanics from Colorado. SUBJECTS AND METHODS: The C1858T single-nucleotide polymorphism within the PTPN22 gene was genotyped in 753 patients with T1D ascertained from the diabetes clinic at the Barbara Davis Center in Denver and 662 control population. RESULTS: Both the PTPN22 CT genotype [odds ratio (OR) = 1.96; p < 0.0001] and TT genotype (OR = 4.41; p = 0.02) were significantly associated with T1D in the NHW population. While the association was stronger in subjects with non-HLA-DR3/4 genotypes than in those with the HLA-DR3/4 genotype, regression analyses did not reveal significant interaction between PTPN22 genotypes and HLA-DR3/4. The strength of the association was similar in males and females, patients diagnosed before and after age 10 yr, and in Hispanics and NHWs. CONCLUSION: In this study, we confirm that PTPN22 is associated with T1D in the Colorado population.