| 1. |
- Endesfelder, David, et al.
(författare)
-
Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children
- 2019
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:1, s. 119-130
-
Tidskriftsartikel (refereegranskat)abstract
- Progression to clinical type 1 diabetes varies among children who develop b-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar profiles associated with various types of progression among 600 children from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study; these children developed persistent insulin autoantibodies (IAA), GAD autoantibodies (GADA), insulinoma-associated antigen 2 autoantibodies (IA-2A), or a combination of these, and they were followed up prospectively at 3- to 6-month intervals (median follow-up 6.5 years). Children who developed multiple autoantibody types (n = 370) were clustered, and progression from seroconversion to clinical diabetes within 5 years ranged between clusters from 6% (95% CI 0, 17.4) to 84% (59.2, 93.6). Children who seroconverted early in life (median age <2 years) and developed IAA and IA-2A that were stable-positive on follow-up had the highest risk of diabetes, and this risk was unaffected by GADA status. Clusters of children who lacked stable-positive GADA responses contained more boys and lower frequencies of the HLA-DR3 allele. Our novel algorithm allows refined grouping of b-cell autoantibody–positive children who distinctly progressed to clinical type 1 diabetes, and it provides new opportunities in searching for etiological factors and elucidating complex disease mechanisms.
|
|
| 2. |
- Hippich, Markus, et al.
(författare)
-
Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families
- 2019
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:4, s. 847-857
-
Tidskriftsartikel (refereegranskat)abstract
- The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.
|
|
| 3. |
- Krischer, Jeffrey P., et al.
(författare)
-
The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History to the Progression from Multiple Autoantibodies to Type 1 Diabetes:A TEDDY Study Report : A TEDDY Study Report
- 2017
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:12, s. 3122-3129
-
Tidskriftsartikel (refereegranskat)abstract
- This paper seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to T1D risk among autoantibody positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium. The risk of progression to T1D was not different among those with or without a family history of T1D (p=0.39) nor HLA-DR-DQ genotypes (p=0.74). Age at developing multiple autoantibodies (HR=0.96 per 1 month increase in age, 95% CI=0.95, 0.97, p<0.001) and the type of first autoantibody (when more than a single autoantibody was the first appearing indication of seroconversion [p=0.006]) were statistically significant. Female sex was also a significant risk factor (p=0.03). Three SNPs were associated with increased diabetes risk (rs10517086_A, [p=0.03], rs1534422_G, [p=0.006], and rs2327832_G in TNFAIP3 [p=0.03]), and one with decreased risk (rs1004446_A in INS, [p=0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.
|
|
| 4. |
- Larsson, Helena Elding, et al.
(författare)
-
Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood : The environmental determinants of diabetes in the young study
- 2016
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:7, s. 1988-1995
-
Tidskriftsartikel (refereegranskat)abstract
- Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight or height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk for type 1 diabetes followed in Finland, Germany, Sweden, and the U.S. Growth data collected every third month were used to estimate individual growth curves by mixed models. Cox proportional hazards models were used to evaluate body size and risk of islet autoimmunity and type 1 diabetes. In the overall cohort, development of islet autoimmunity (n = 575) was related to weight z scores at 12 months (hazard ratio [HR] 1.16 per 1.14 kg in males or per 1.02 kg in females, 95% CI 1.06-1.27, P <0.001, false discovery rate [FDR] = 0.008) but not at 24 or 36 months. A similar relationship was seen between weight z scores and development of multiple islet autoantibodies (1 year: HR 1.21, 95% CI 1.08-1.35, P = 0.001, FDR = 0.008; 2 years: HR 1.18, 95% CI 1.06-1.32, P = 0.004, FDR = 0.02). No association was found between weight or height and type 1 diabetes (n = 169). In conclusion, greater weight in the first years of life was associated with an increased risk of islet autoimmunity.
|
|
| 5. |
- Norris, Jill M., et al.
(författare)
-
Plasma 25-Hydroxyvitamin D concentration and risk of islet autoimmunity
- 2018
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:1, s. 146-154
-
Tidskriftsartikel (refereegranskat)abstract
- We examined the association between plasma 25- hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested casecontrol study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentrationwas measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.
|
|
| 6. |
- Törn, Carina, et al.
(författare)
-
Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY Study.
- 2015
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:5, s. 1818-1829
-
Tidskriftsartikel (refereegranskat)abstract
- The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p<0.05), whereof four were significant after adjustment for multiple testing (p<0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.
|
|
