Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes: The TEDDY Study

Children’s plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.

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Plasma metabolome and circulating vitamins stratified onset age of an initial islet autoantibody and progression to type 1 diabetes: the TEDDY study

10.2337/figshare.13122524.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Qian Li ◽

Xiang Liu ◽

Jimin Yang ◽

Iris Erlund ◽

...

Keyword(s):

Ascorbic Acid ◽

Type 1 Diabetes ◽

Early Onset ◽

Acid Decarboxylase ◽

Islet Autoantibody ◽

Differential Analysis ◽

Plasma Ascorbic Acid ◽

Hydroxyvitamin D ◽

Plasma Metabolome

Children’s plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.

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Faculty Opinions recommendation of Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012861.187509 ◽

2003 ◽

Author(s):

Jin-Xiong She

Keyword(s):

Type 1 Diabetes ◽

Onset Age ◽

Genetic Liability ◽

Follow Up Study

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HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes

Diabetologia ◽

10.1007/s00125-021-05476-6 ◽

2021 ◽

Author(s):

Ziyu Jiang ◽

Wenqian Ren ◽

Hua Liang ◽

Jinhua Yan ◽

Daizhi Yang ◽

...

Keyword(s):

Type 1 Diabetes ◽

Disease Risk ◽

Hla Class I ◽

Class I ◽

Chinese Patients ◽

Onset Age ◽

Disease Heterogeneity ◽

Negatively Associated ◽

Healthy Control

Abstract Aims/hypothesis The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. Methods A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. Results The susceptible DR3 (β = −0.09, p = 0.0009) and DR4-DQ8 (β = −0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = −0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. Conclusions/interpretation In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies. Graphical abstract

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243-OR: Integrating Genetic Risk Score and Islet Autoantibody Characteristics in the Predictive Model for Type 1 Diabetes in the TrialNet Study

Diabetes ◽

10.2337/db21-243-or ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 243-OR

Author(s):

LAURIC A. FERRAT ◽

ANDREA STECK ◽

HEMANG M. PARIKH ◽

LU YOU ◽

SUNA ONENGUT-GUMUSCU ◽

...

Keyword(s):

Type 1 Diabetes ◽

Predictive Model ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Islet Autoantibody

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Stratification of Type 1 Diabetes Risk on the Basis of Islet Autoantibody Characteristics

Diabetes ◽

10.2337/diabetes.53.2.384 ◽

2004 ◽

Vol 53 (2) ◽

pp. 384-392 ◽

Cited By ~ 171

Author(s):

P. Achenbach ◽

K. Warncke ◽

J. Reiter ◽

H. E. Naserke ◽

A. J.K. Williams ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Risk ◽

Islet Autoantibody

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An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

10.2337/figshare.13643756 ◽

2021 ◽

Author(s):

Ezio Bonifacio ◽

Andreas Weiß ◽

Christiane Winkler ◽

Markus Hippich ◽

Marian J. Rewers ◽

...

Keyword(s):

Type 1 Diabetes ◽

Confidence Interval ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Age Related ◽

At Risk Children ◽

Exponential Decline ◽

Design And Methods

Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes. Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

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Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105532 ◽

2018 ◽

Vol 56 (9) ◽

pp. 602-605 ◽

Cited By ~ 4

Author(s):

Andreas Beyerlein ◽

Ezio Bonifacio ◽

Kendra Vehik ◽

Markus Hippich ◽

Christiane Winkler ◽

...

Keyword(s):

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Genetic Factors ◽

Genetic Risk Score ◽

Risk Scores ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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Body Mass Index and Mortality in Individuals With Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00042 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5195-5204 ◽

Cited By ~ 1

Author(s):

Emma H Dahlström ◽

Niina Sandholm ◽

Carol M Forsblom ◽

Lena M Thorn ◽

Fanny J Jansson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Excretion Rate ◽

Albumin Excretion Rate ◽

Normal Weight ◽

Onset Age ◽

Diabetes Onset ◽

Risk Of Mortality ◽

The Relationship ◽

Normal Albumin

Abstract Context The relationship between body mass index (BMI) and mortality may differ between patients with type 1 diabetes and the general population; it is not known which clinical characteristics modify the relationship. Objective Our aim was to assess the relationship between BMI and mortality and the interaction with clinically meaningful factors. Design, Setting, and Participants This prospective study included 5836 individuals with type 1 diabetes from the FinnDiane study. Main Outcome Measure and Methods We retrieved death data for all participants on 31 December 2015. We estimated the effect of BMI on the risk of mortality using a Cox proportional hazards model with BMI as a restricted cubic spline as well as effect modification by adding interaction terms to the spline. Results During a median of 13.7 years, 876 individuals died. The relationship between baseline BMI and all-cause mortality was reverse J-shaped. When analyses were restricted to those with normal albumin excretion rate, the relationship was U-shaped. The nadir BMI (BMI with the lowest mortality) was in the normal weight region (24.3 to 24.8 kg/m2); however, among individuals with diabetic nephropathy, the nadir BMI was in the overweight region (25.9 to 26.1 kg/m2). Diabetic nephropathy, diabetes-onset age, and sex modified the relationship between BMI and mortality (Pinteraction < 0.05). Conclusions Normal weight is optimal for individuals with type 1 diabetes to delay mortality, whereas underweight might be an indication of underlying complications. Maintaining normal weight may translate into reduced risk of mortality in type 1 diabetes, particularly for individuals of male sex, later diabetes-onset age, and normal albumin excretion rate.

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A strategy to find gene combinations that identify children who progress rapidly to type 1 diabetes after islet autoantibody seroconversion

Acta Diabetologica ◽

10.1007/s00592-013-0526-2 ◽

2013 ◽

Vol 51 (3) ◽

pp. 403-411 ◽

Cited By ~ 17

Author(s):

Ezio Bonifacio ◽

Jan Krumsiek ◽

Christiane Winkler ◽

Fabian J. Theis ◽

Anette-Gabriele Ziegler

Keyword(s):

Type 1 Diabetes ◽

Islet Autoantibody

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