scholarly journals Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Suna Onengut-Gumuscu ◽  
Umadevi Paila ◽  
Wei-Min Chen ◽  
Aakrosh Ratan ◽  
Zhennan Zhu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Viral Infections ◽  
Genetic Risk Factors ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Critical Pathways ◽  
Genome Wide

Abstract 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 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10–8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.

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

2018 ◽  
Vol 56 (9) ◽  
pp. 602-605 ◽  
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.

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study

Diabetes Care ◽  
2021 ◽  
pp. dc202388
Author(s):  
Ionut Bebu ◽  
Sareh Keshavarzi ◽  
Xiaoyu Gao ◽  
Barbara H. Braffett ◽  
Angelo J. Canty ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Genetic Risk Factors

scholarly journals Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes

2015 ◽  
Vol 32 (8) ◽  
pp. 1104-1109 ◽  
Author(s):  
E. J. Swan ◽  
R. M. Salem ◽  
N. Sandholm ◽  
L. Tarnow ◽  
P. Rossing ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Mitochondrial Function ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Factors Affecting

Genetic risk factors for type 1 diabetes

The Lancet ◽  
2016 ◽  
Vol 387 (10035) ◽  
pp. 2331-2339 ◽  
Author(s):  
Flemming Pociot ◽  
Åke Lernmark
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Genetic Risk Factors

General population screening for childhood type 1 diabetes: is it time for a UK strategy?

2021 ◽  
pp. archdischild-2021-321864
Author(s):  
Rachel Elizabeth Jane Besser ◽  
Sze May Ng ◽  
John W Gregory ◽  
Colin M Dayan ◽  
Tabitha Randell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Population Based ◽  
Screening Strategy ◽  
Smooth Transition ◽  
Islet Autoantibodies ◽  
Awareness Campaigns

Type 1 diabetes (T1D) is a chronic autoimmune disease of childhood affecting 1:500 children aged under 15 years, with around 25% presenting with life-threatening diabetic ketoacidosis (DKA). While first-degree relatives have the highest risk of T1D, more than 85% of children who develop T1D do not have a family history. Despite public health awareness campaigns, DKA rates have not fallen over the last decade. T1D has a long prodrome, and it is now possible to identify children who go on to develop T1D with a high degree of certainty. The reasons for identifying children presymptomatically include prevention of DKA and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression. Research studies of population-based screening strategies include using islet autoantibodies alone or in combination with genetic risk factors, both of which can be measured from a capillary sample. If found during screening, the presence of two or more islet autoantibodies has a high positive predictive value for future T1D in childhood (under 18 years), offering an opportunity for DKA prevention. However, a single time-point test will not identify all children who go on to develop T1D, and so combining with genetic risk factors for T1D may be an alternative approach. Here we discuss the pros and cons of T1D screening in the UK, the different strategies available, the knowledge gaps and why a T1D screening strategy is needed.

scholarly journals Prediction of autoimmune diabetes and celiac disease in childhood by genes and perinatal environment: Design and initial aims of the PAGE study

2014 ◽  
Vol 24 (1-2) ◽  
Author(s):  
Lars C. Stene ◽  
Geir Joner ◽  
Ketil Størdal
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Blood Plasma ◽  
Genetic Risk ◽  
Autoimmune Diabetes ◽  
Genetic Risk Factors ◽  
Host Cells ◽  
Full Cohort

Type 1 diabetes and celiac disease result from misdirected immune mediated destruction of host cells, and are among the most common chronic diseases in children. Despite changes in incidence over the past 3 decades, little is known about non-genetic risk factors (except for dietary gluten for celiac disease). Norway is among the countries in the world with the highest incidence of these two diseases. We describe here plans and study design for the PAGE study (Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment). PAGE is a sub-study within the Norwegian Mother and Child Cohort study, including follow-up of more than 100,000 pregnancies. Children who develop type 1 diabetes or celiac disease are identified via linkage to the Norwegian Patient Register and the Norwegian Childhood Diabetes Registry, with complementing information from questionnaires. The overall aim is to test hypotheses about potential non-genetic risk factors for type 1 diabetes and for celiac disease, with focus on factors operating early in life. In addition to a full cohort analysis of factors registered in questionnaires, we will analyse biomarkers in maternal blood plasma and cord blood plasma. Mothers and children will be genotyped for well-established susceptibility polymorphisms. Biomarkers will be analysed in cases and controls within the cohort. Factors to be tested in the full cohort include infant feeding, diet and dietary supplements in the mother during pregnancy and in the child, and use of antibiotics and non-prescription drugs. Biomarkers to be tested include 25-hydroxyvitamin D, markers of immune activation, and small metabolites (metabolomics). We will also explore the potential role of maternal cells in the fetal circulation (maternal microchimerism) in later risk of celiac disease and type 1 diabetes.

107-OR: Novel Genetic Risk Factors Influence Islet Autoimmunity Progression

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 107-OR
Author(s):  
SUNA ONENGUT-GUMUSCU ◽  
UMA DEVI PAILA ◽  
WEI-MIN CHEN ◽  
AAKROSH RATAN ◽  
ZHENNAN ZHU ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Islet Autoimmunity

P6017 A high density genome-wide scan for genetic risk factors of insect bite hypersensitivity (IBH): A Horsegene Project Initiative

2016 ◽  
Vol 94 (suppl_4) ◽  
pp. 156-157
Author(s):  
B. D. Velie ◽  
M. Shrestha ◽  
L. Francois ◽  
A. Schurink ◽  
A. Stinckens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
High Density ◽  
Genome Wide ◽  
Insect Bite Hypersensitivity ◽  
Genome Wide Scan

scholarly journals Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

2021 ◽  
Vol 9 (7) ◽  
pp. 1519
Author(s):  
Sonia R. Isaacs ◽  
Dylan B. Foskett ◽  
Anna J. Maxwell ◽  
Emily J. Ward ◽  
Clare L. Faulkner ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Virus Detection ◽  
Detection Methods ◽  
Islet Autoimmunity ◽  
Comprehensive Overview ◽  
Drug Candidates

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

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