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Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications (ISIS-DIAB)

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ClinicalTrials.gov Identifier: NCT02212522
Recruitment Status : Unknown
Verified June 2016 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was:  Recruiting
First Posted : August 8, 2014
Last Update Posted : June 28, 2016
Sponsor:
Collaborators:
Centre National de Génotypage
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

The aim of this study is to complete the identification of genetic factors (G) and to undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G analysis (whole genome genotyping done once a patient using methods conually updated at Centre National de Genotype) and innovative E analysis to develop the following long term objectives :

  • Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years diabetes duration);
  • Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients with negative C-peptide and well managed diabetes);
  • Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents;
  • Undertake a prospective research of G and E risk factors of incipient glomerular microangiopathy (regule measurement of microalbuminuria).

Condition or disease Intervention/treatment
Diabetes Mellitus Insulin-Dependent Other: Collect of environmental data on T1D patients before diagnosis Genetic: Collect of blood samples for DNA extraction and genetic characterization (GWAS) Other: Collect of clinical data on the disease and its evolution Other: Collect of environmental data on French controls (age-matched for T1D patients)

Detailed Description:

Still recognized in youth only at a stage of complete beta-cell mass destruction and insulin deficiency, autoimmune T1D remains a source of major morbidity through daily life and chronic angiopathic complications despite a better glycemic control. T1D onset is now predominantly pediatric, since its incidence shows a rapid and continuous increase in young European children, due to unknown emerging environmental changes, creating a major need for discoveries in the environmental field. Finding avoidable E factors can allow T1D prevention in the whole children population. Lack of infectious exposures ("the hygiene hypothesis"), viruses, early nutrition, or other factors have been suspected, but E causes of T1D remain a black box, as for most human diseases, that should now be approached more systematically and with respect to gene-environment interactions.

The aim of our study is to complete the identification of genetic factors (G) and to undertake the search of environmental factors (E) predisposing to type 1 diabetes (T1D) by constituting a cohort of 3500 T1D patients and a control cohort. We will use the base of G analysis (whole genome genotyping done once a patient using methods conually updated at Centre National de Genotype) and innovative E analysis to develop the following long term objectives :

  • Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis (subgroup of T1D patients with a 0-3 years diabetes duration);
  • Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years (subgroup of T1D patients with negative C-peptide and well managed diabetes);
  • Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents;
  • Undertake a prospective research of G and E risk factors of incipient glomerular microangiopathy (regule measurement of microalbuminuria).

We propose to constitute a French multicentric cohort of T1D patients, well phenotyped by 3 data types : genetic, environmental and clinical data. The data collection scheme includes at entry a comprehensive 850 items environmental questionnaire for all subjects and a full genotyping with at least 500,000 SNPs until whole-genome sequencing can be deployed by CNG-CEA. Every 6 months, a standardized clinical assessment is made in patients (a WEB application ensuring this standardization has already been developed). Personal address(es) will be collected and geocoded, then mapped with environmental geographic information systems (GIS).

With environmental modelling, the high dimensionality analyses (HDA) constitutes one of the main originality of ISIS-DIAB approaches of translational research. HDA will face not only a massive mass of data, but data of a remarkable diversity (genomic variants, environmental items from questionnaires, environmental data bases mapped to patient address, space-time items, characteristics of social environment, clinical phenotypes etc). A given genotype (defined by many genomic variants) will predispose to T1D only in a given environmental context (defined possibly by a number of factors) and induce a given type of autoimmune process (age of onset, rate of destruction, biomarkers). Since T1D is both multifactorial and heterogeneous, causal factors may interact in a considerable number of scenarii, thus platforms which study these factors should obviously interact. Without HDA, each platform would be left faced with its own data. The chef d'orchestre has to be HDA, to integrate the massive amounts of data and draw networks of causality. Technological advances in HDA developed in other fields of sciences, business and economics (forecasting technology) will be transferred to biomedical research through ISIS-DIAB. French have a strong tradition of high-level maths in this area. We designed the ISIS-DIAB cohort and collection of data to feed HDA with multidisciplinary data. In ISIS-DIAB program, HDA will identify the variables that have the most predictive value on several outcomes (not confined to T1D causality).


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Study Type : Observational
Estimated Enrollment : 20000 participants
Observational Model: Case Control
Official Title: Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications. French Multicentric Cohort of Diabetic Patients.
Study Start Date : November 2004
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Isis-Diab patients
French T1D patients with genetic data (GWAS), and environmental data (questionnaire and environmental databases), clinical data
Other: Collect of environmental data on T1D patients before diagnosis
Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data

Genetic: Collect of blood samples for DNA extraction and genetic characterization (GWAS)
Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)

Other: Collect of clinical data on the disease and its evolution
Collect of clinical data on the disease and its evolution every 6 months after enrollment

Isis-Diab controls
French control population with genetic data (GWAS) and environmental data (questionnaire and environmental databases
Other: Collect of environmental data on French controls (age-matched for T1D patients)
Questionnaires on large environment during mother's pregnancy and patient's childhood, health book copies, addresses' geolocation, quantification of viral exposures using Sentinel Network data

Genetic: Collect of blood samples for DNA extraction and genetic characterization (GWAS)
Collect of blood samples for DNA extraction and genetic characterization (GWAS) on Illumina platform (Centre National de Genotype)




Primary Outcome Measures :
  1. Genetic and environmental risk factors of T1D predisposition [ Time Frame: 10 years ]

Secondary Outcome Measures :
  1. Genetic and environmental risk factors of T1D complications [ Time Frame: 10 years ]
    Regular measurement of microalbuminuria

  2. Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis [ Time Frame: 5 years ]
    Subgroup of T1D patients with a 0-3 years diabetes duration

  3. Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years [ Time Frame: 4 years ]
    Subgroup of T1D patients with negative C-peptide and well managed diabetes

  4. Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents [ Time Frame: 5 years ]

Biospecimen Retention:   Samples With DNA
whole blood


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Patients: T1D patients are enrolled into the Isis-Diab cohort, continuously, from 110 clinical diabetes centers distributed over the whole France territory. Inclusion in the cohort occurs most often soon after the initial diagnosis of T1D. This diagnosis is made according to classical criteria of autoimmune T1D.

Controls: we will recruit age-matched controls among friend patients' families and among cases admitted in the participating centers for benign transient intercurrent events.

Criteria

Inclusion Criteria:

  • Insulin-dependent diabetes
  • Patients older than 6 months at inclusion
  • European or North African geographical origin (defined by the birthplaces of the 4 grandparents), for the purpose of genetic homogeneity of the cohort
  • Anti-GAD, IA2, and insulin autoantibodies, that are present only in the first year of the disease evolution, are not a criterion of absolute inclusion (low risk of error) but will be noted if they were searched at diagnosis
  • Informed consent dated and voluntarily signed (patient and/or parents)

Exclusion Criteria:

  • Non-insulin dependent diabetes
  • MODY
  • Severe psychological problems, co-morbidities that could possibly invalidate informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02212522


Contacts
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Contact: Sophie Le Fur, PhD +33 1 49 59 53 43 sophie.le-fur@inserm.fr
Contact: Laurence LECOMTE, PhD +33 1 71 19 64 94 laurence.lecomte@nck.aphp.fr

Locations
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France
Inserm U986 Recruiting
Le Kremlin Bicêtre, France, 94276
Contact: Sophie Le Fur, PhD    + 33 1 49 59 53 43    sophie.le-fur@inserm.fr   
Contact: Laurence Lecomte, PhD    +33 1 71 19 64 94    laurence.lecomte@nck.aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Centre National de Génotypage
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Principal Investigator: Pierre BOUGNERES, MD-PhD Inserm U986/ Pediatric endocrinology department of the Bicêtre hospital

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02212522     History of Changes
Other Study ID Numbers: AOM 08049
First Posted: August 8, 2014    Key Record Dates
Last Update Posted: June 28, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Diabetes Mellitus
Insulin-Dependent
Genome-Wide Association Study
Environment-Wide Association Study
Predisposition
Complications
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases