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In addition to the HLA region numerous other gene loci have shown association with type 1 diabetes. How these polymorphisms exert their function has not been comprehensively described, however. We assessed the effect of 39 single nucleotide polymorphisms (SNP) on the development of autoantibody positivity, on progression from autoantibody positivity to clinical disease and on the specificity of the antibody initiating the autoimmune process in 521 autoantibody-positive and 989 control children from a follow-up study starting from birth. Interestingly, PTPN2 rs45450798 gene polymorphism was observed to strongly affect the progression rate of beta-cell destruction after the appearance of humoral beta-cell autoimmunity. Moreover, primary autoantigen dependent associations were also observed as effect of the IKZF4-ERBB3 region on the progression rate of β-cell destruction was restricted to children with GAD antibodies as their first autoantibody whereas the effect of the INS rs 689 polymorphism was observed among subjects with insulin as the primary autoantigen. In the whole study cohort, INS rs689, PTPN22 rs2476601 and IFIH1 rs1990760 polymorphisms were associated with the appearance of beta-cell autoantibodies. These findings provide new insights into the role of genetic factors implicated in the pathogenesis of type 1 diabetes. The effect of some of the gene variants is restricted to control the initiation of β-cell autoimmunity whereas others modify the destruction rate of the β-cells. Furthermore, signs of primary autoantigen-related pathways were detected.

Prediction of type 1 diabetes is based on the detection of multiple islet autoantibodies in subjects who are at increased genetic risk. Prediction of the timing of diagnosis is challenging, however. We assessed the utility of HbA1c levels in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. Cord blood samples from 168,055 newborn infants were screened for class II HLA genotypes in Finland, and 14,876 children with increased genetic risk for type 1 diabetes were invited to participate in regular follow-ups, including screening for diabetes-associated autoantibodies. When two or more autoantibodies were detected, HbA1c levels were analyzed at each visit. During follow-up, multiple (two or more) autoantibodies developed in 466 children; type 1 diabetes was diagnosed in 201 of these children (43%, progressors), while 265 children remained disease free (nonprogressors) by December 2011. A 10% increase in HbA1c levels in samples obtained 3–12 months apart predicted the diagnosis of clinical disease (hazard ratio [HR] 5.7 [95% CI 4.1–7.9]) after a median time of 1.1 years (interquartile range [IQR] 0.6–3.1 years) from the observed rise of HbA1c. If the HbA1c level was ≥5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years (IQR 0.3–1.5, HR 11.9 [95% CI 8.8–16.0]). In conclusion, HbA1c is a useful biochemical marker when predicting the time to diagnosis of type 1 diabetes in children with multiple autoantibodies.

Type 1 diabetes (T1D) is an autoimmune disease causing the destruction of pancreatic beta cells. The onset of clinical T1D is preceded by a time period called pre-diabetes, the duration of which varies widely. However, not all subjects developing beta-cell autoimmunity progress to clinical T1D. The inherited risk for T1D is determined by the human leukocyte antigen (HLA) class II genes, HLA class I genes, and several loci outside the HLA area. Although the role of the genetic risk variants in disease pathogenesis is not completely understood, some of the variants affecting disease risk are thought to influence the initiation of beta-cell autoimmunity whereas others seem to play a role during the later stages of the autoimmune process. In this review we describe the current knowledge on the genetic factors mediating the fate of already-established beta-cell autoimmunity and the rate of beta-cell destruction.

Genetic heterogeneity may affect the analysis of risk factors associated with type 1 diabetes (T1D). We studied the effect of the INS -23A/T, PTPN22 1858C/T, and CTLA-4 +49A/G polymorphisms on the emergence of T1D-associated autoimmunity in children exposed to cow's milk (CM) based formula during early or late infancy. The study comprised of 156 children from the Finnish DIPP cohort who had developed >or= 2 types of autoantibodies (ICA, IAA, GADA or IA-2A) or clinical T1D and 563 control children. The PTPN22 1858T allele was associated with the appearance of the autoantibodies and clinical T1D among children exposed to CM formula before the age of 6 months (PTPN22: for all P

IMPORTANCE: Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain. OBJECTIVE: To determine the rate of progression to diabetes after islet autoantibody seroconversion. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012. MAIN OUTCOMES AND MEASURES: The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies. RESULTS: Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]). CONCLUSIONS AND RELEVANCE: The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.