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

June 27, 2016 updated by: Assistance Publique - Hôpitaux de Paris

Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications. French Multicentric Cohort of Diabetic Patients.

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).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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).

Study Type

Observational

Enrollment (Anticipated)

20000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

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
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 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Genetic and environmental risk factors of T1D predisposition
Time Frame: 10 years
10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genetic and environmental risk factors of T1D complications
Time Frame: 10 years
Regular measurement of microalbuminuria
10 years
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
5 years
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 years
Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents
Time Frame: 5 years
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France
Centre National de Génotypage

Investigators

  • Principal Investigator: Pierre BOUGNERES, MD-PhD, Inserm U986/ Pediatric endocrinology department of the Bicêtre hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2004

Primary Completion (Anticipated)

December 1, 2017

Study Completion (Anticipated)

June 1, 2018

Study Registration Dates

First Submitted

August 6, 2014

First Submitted That Met QC Criteria

August 6, 2014

First Posted (Estimate)

August 8, 2014

Study Record Updates

Last Update Posted (Estimate)

June 28, 2016

Last Update Submitted That Met QC Criteria

June 27, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AOM 08049

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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