Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes.
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ABSTRACT:
SUBMITTER: Onengut-Gumuscu S
PROVIDER: S-EPMC7645414 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes.
Onengut-Gumuscu Suna S Paila Umadevi U Chen Wei-Min WM Ratan Aakrosh A Zhu Zhennan Z Steck Andrea K AK Frohnert Brigitte I BI Waugh Kathleen C KC Webb-Robertson Bobbie-Jo M BM Norris Jill M JM Lange Leslie A LA Rewers Marian J MJ Rich Stephen S SS
Scientific reports 20201105 1
Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 di ...[more]
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Project description:ObjectiveWe tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.Research design and methodsWe studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.ResultsHigher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).ConclusionsThe T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
| S-EPMC6105323 | biostudies-literature
Project description:BACKGROUND:Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. METHODS:In 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. RESULTS:Islet 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). CONCLUSIONS:Genetic 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.
| S-EPMC6690814 | biostudies-literature
Project description:Aims/hypothesisWe hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals.MethodsIn this study, we analysed the data from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white [NHW], 2.9% non-Hispanic black [NHB] and 5.2% non-Hispanic other [NHO]). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis.ResultsConversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 [95% CI 0.46, 0.96], p = 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and HLA-DR3-DQ2/DR4-DQ8 genotype. In participants who screened positive for multiple autoantibodies (n = 2834), time to type 1 diabetes did not differ by race/ethnicity overall (p = 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 [95% CI 1.04, 1.77], p = 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 [95% CI 1.6, 9.1], p = 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity.Conclusions/interpretationThe risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI.
| S-EPMC6611550 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group. METHODS:We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS. RESULTS:In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids. CONCLUSIONS/INTERPRETATION:Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.
| S-EPMC6861356 | biostudies-literature
Project description:Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
| S-EPMC6359525 | biostudies-literature
Project description:Type 1 Diabetes (T1D) results from autoimmune destruction of insulin producing pancreatic ß-cells. This disease, with a peak incidence in childhood, causes the lifelong need for insulin injections and necessitates careful monitoring of blood glucose levels. However, despite the current insulin therapies, it still shortens life expectancy due to complications affecting multiple organs. Recently, the incidence of T1D in childhood has increased by 3-5% per year in most developed Western countries. The heterogeneity of the disease process is supported by the findings of follow-up studies started early in infancy. The development of T1D is usually preceded by the appearance of autoantibodies targeted against antigens expressed in the pancreatic islets. The risk of T1D increases significantly with an increasing number of positive autoantibodies. The order of autoantibody appearance affects the disease risk. Genetic susceptibility, mainly defined by the human leukocyte antigen (HLA) class II gene region and environmental factors, is important in the development of islet autoimmunity and T1D. Environmental factors, mainly those linked to the changes in the gut microbiome as well as several pathogens, especially viruses, and diet are key modulators of T1D. The aim of this paper is to expand the understanding of the aetiology and pathogenesis of T1D in childhood by detailed description and comparison of factors affecting the progression from the islet autoimmunity to T1D in children.
| S-EPMC8305179 | biostudies-literature
Project description:<h4><strong>AIMS/HYPOTHESIS: </strong>Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.</h4><h4><strong>METHODS: </strong>We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.</h4><h4><strong>RESULTS: </strong>In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.</h4><h4><strong>CONCLUSIONS/INTERPRETATION: </strong>Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.</h4>
2022-01-19 | MTBLS802 | MetaboLights
Project description:ObjectiveThere are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.Research design and methodsSubjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.ResultsAt screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.ConclusionsRisk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
| S-EPMC6341285 | biostudies-literature
Project description:To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies.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.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.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.
| S-EPMC2992780 | biostudies-literature
Project description:ContextVitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases.ObjectiveThe objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D.DesignThe Diabetes Autoimmunity Study in the Young is a longitudinal, observational study.SettingNewborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado.ParticipantsA total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D.Main outcome measuresIA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures.ResultsThe risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 [hazard ratio 1.36, 95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels.ConclusionsDHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.
| S-EPMC3816262 | biostudies-literature