Dynamic changes in immune gene co-expression networks predict development of type 1 diabetes

AbstractSignificant progress has been made in elucidating genetic risk factors influencing Type 1 diabetes (T1D); however, features other than genetic variants that initiate and/or accelerate islet autoimmunity that lead to the development of clinical T1D remain largely unknown. We hypothesized that genetic and environmental risk factors can both contribute to T1D through dynamic alterations of molecular interactions in physiologic networks. To test this hypothesis, we utilized longitudinal blood transcriptomic profiles in The Environmental Determinants of Diabetes in the Young (TEDDY) study to generate gene co-expression networks. In network modules that contain immune response genes associated with T1D, we observed highly dynamic differences in module connectivity in the 600 days (~ 2 years) preceding clinical diagnosis of T1D. Our results suggest that gene co-expression is highly plastic and that connectivity differences in T1D-associated immune system genes influence the timing and development of clinical disease.

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Prospective evaluation of risk factors for the development of islet autoimmunity and type 1 diabetes during puberty - TEENDIAB: study design

Pediatric Diabetes ◽

10.1111/j.1399-5448.2011.00763.x ◽

2011 ◽

Vol 13 (5) ◽

pp. 419-424 ◽

Cited By ~ 26

Author(s):

Anette-Gabriele Ziegler ◽

Franziska Meier-Stiegen ◽

Christiane Winkler ◽

Ezio Bonifacio ◽

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Study Design ◽

Islet Autoimmunity ◽

Prospective Evaluation

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Factors of raised C-reactive protein as a potential determinant of Diabetic patients and Risk factor for Coronary Heart Disease

International Journal Of Medical Science And Clinical Invention ◽

10.18535/ijmsci/v5i3.18 ◽

2018 ◽

Vol 5 (3) ◽

pp. 3656-3661

Author(s):

Sharma Sushil Kumar ◽

Rastogi Parag

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Type 1 Diabetes ◽

Heart Disease ◽

Research Work ◽

Islet Autoimmunity ◽

Diabetic Patients ◽

C Reactive Protein ◽

Reactive Protein

Elevated C-reactive protein (CRP) levels have previously been described before the onset of type 1 diabetes and gestational diabetes. We hypothesized that inflammation, as reflected by elevated CRP levels, can help predict development of islet autoimmunity or type 1 diabetes. The outcome of this research is to establish potential determinants of raised CRP concentrations in type 1 diabetic patients. Sensitive assay showed ‘low-level’ CRP concentrations in 147 type 1 patients (83M, 64F, median age 30 years, range 13–67). We have done step by step variant examination to relate these CRP levels to known cardiovascular risk factors and demographic data. Only four patients had established Coronary Heart Disease (median CRP 3.43 mg/l vs. 0.85 mg/l, p=0.035). In subjects without overt CHD, multivariate analysis revealed increase in subject age (p=0.0027), BMI (p=0.001) and HbA1 (p=0.013) to be associated with a higher CRP concentration, as was female sex (p=0.025) and a history of CHD in a first-degree relative (p=0.018, n=58). Elevated CRP levels were positively associated with cardiovascular and renal risk factors: age, body mass index, blood pressure, serum cholesterol level, smoking, plasma glucose level and elevated urinary albumin excretion and presence of hypertension were unrelated. This research work advises that certain of the risk factors connected with CHD in type 1 patients are also individually predictive of high CRP concentrations. The reasons for this, and whether intervention would prove valuable, require further analysis

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

Scientific Reports ◽

10.1038/s41598-020-75690-6 ◽

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.

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