Telomere Length is Not a Main factor for the Development of Islet Autoimmunity and Type 1 Diabetes in the TEDDY Study

Abstract The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 children, 3-4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1,119 children in a nested case-control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR: 4.52 kb – 5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.

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Association of high-affinity autoantibodies with type 1 diabetes high-risk HLA haplotypes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab853 ◽

2021 ◽

Author(s):

Taylor M Triolo ◽

Laura Pyle ◽

Hali Broncucia ◽

Taylor Armstrong ◽

Liping Yu ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Islet Autoimmunity ◽

Initial Visit ◽

Prevention Study ◽

High Affinity ◽

Z Scores ◽

Hla Haplotypes ◽

Hla Dr3

Abstract Objective ECL assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk HLA haplotypes and genotypes with electrochemiluminescence (ECL) positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab (GADA or IAA) and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (Z-scores) for analyses. Results Mean age at initial visit was 19.4+13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA- DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all p<0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both p<0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (p<0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

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Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: the TEDDY study

Diabetologia ◽

10.1007/s00125-019-05028-z ◽

2019 ◽

Vol 63 (2) ◽

pp. 278-286 ◽

Cited By ~ 2

Author(s):

Markus Mattila ◽

◽

Iris Erlund ◽

Hye-Seung Lee ◽

Sari Niinistö ◽

...

Keyword(s):

Ascorbic Acid ◽

Type 1 Diabetes ◽

Vitamin C ◽

Data Availability ◽

Islet Autoimmunity ◽

Plasma Ascorbic Acid ◽

Background Population ◽

Increased Risk ◽

Nested Case Control

Abstract Aims/hypothesis We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes. Methods We used a risk set sampled nested case–control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification. Results Childhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]). Conclusions/interpretation Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings. Data availability The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.

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