Next steps in the identification of gene targets for type 1 diabetes

Abstract The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment.

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A Comprehensive Type 1 Diabetes Genetic Risk Score Is Associated with Type 2 Diabetes in the Framingham Heart Study

Diabetes ◽

10.2337/db18-1715-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1715-P

Author(s):

SHYLAJA SRINIVASAN ◽

AARON LEONG ◽

MIRIAM UDLER ◽

BIANCA C. PORNEALA ◽

JAMES B. MEIGS ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Framingham Heart Study ◽

Genetic Risk Score ◽

Heart Study

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A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults

Diabetes Care ◽

10.2337/dc15-1111 ◽

2015 ◽

Vol 39 (3) ◽

pp. 337-344 ◽

Cited By ~ 111

Author(s):

Richard A. Oram ◽

Kashyap Patel ◽

Anita Hill ◽

Beverley Shields ◽

Timothy J. McDonald ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Young Adults ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score

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Autoimmunity plays a role in the onset of diabetes after 40 years of age

Diabetologia ◽

10.1007/s00125-019-05016-3 ◽

2019 ◽

Vol 63 (2) ◽

pp. 266-277 ◽

Cited By ~ 3

Author(s):

Olov Rolandsson ◽

Christiane S. Hampe ◽

Stephen J. Sharp ◽

Eva Ardanaz ◽

Heiner Boeing ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Score ◽

Incident Diabetes ◽

Risk Scores ◽

Antibody Positivity ◽

Gad65 Antibody

Abstract Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

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A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody–Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

Diabetes Care ◽

10.2337/dc18-0431 ◽

2018 ◽

Vol 42 (2) ◽

pp. 208-214 ◽

Cited By ~ 12

Author(s):

Anita L. Grubb ◽

Timothy J. McDonald ◽

Femke Rutters ◽

Louise A. Donnelly ◽

Andrew T. Hattersley ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Insulin Therapy ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Positive Type

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Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol

BMJ Open ◽

10.1136/bmjopen-2018-028578 ◽

2019 ◽

Vol 9 (6) ◽

pp. e028578 ◽

Cited By ~ 11

Author(s):

Anette-Gabriele Ziegler ◽

Peter Achenbach ◽

Reinhard Berner ◽

Kristina Casteels ◽

Thomas Danne ◽

...

Keyword(s):

Type 1 Diabetes ◽

Primary Prevention ◽

Beta Cell ◽

Genetic Risk ◽

Autoimmune Diabetes ◽

Genetic Risk Score ◽

Acid Decarboxylase ◽

Oral Insulin ◽

Double Blind

IntroductionThe POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.Methods and analysisInfants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.Ethics and disseminationThe study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.Trial registration numberNCT03364868.

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Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol

BMJ Open ◽

10.1136/bmjopen-2021-052449 ◽

2021 ◽

Vol 11 (11) ◽

pp. e052449

Author(s):

Anette-Gabriele Ziegler ◽

Stefanie Arnolds ◽

Annika Kölln ◽

Peter Achenbach ◽

Reinhard Berner ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Genetic Risk ◽

Autoimmune Diabetes ◽

Genetic Risk Score ◽

Bifidobacterium Longum ◽

Daily Administration ◽

Ethical Review ◽

Acid Decarboxylase

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.

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The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells

Endocrinology ◽

10.1210/endocr/bqz028 ◽

2019 ◽

Vol 161 (2) ◽

Cited By ~ 4

Author(s):

Irina X Zhang ◽

Malini Raghavan ◽

Leslie S Satin

Keyword(s):

Type 2 Diabetes ◽

Endoplasmic Reticulum ◽

Type 1 Diabetes ◽

Beta Cell ◽

Er Stress ◽

Beta Cells ◽

Unfolded Protein ◽

Protein Response

Abstract The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott–Rallison syndrome.

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