Clinical trial NCT02212522: Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications
Official title: Genetic and Environmental Risk Factors of Type 1 Autoimmune Diabetes and Its Early Complications. French Multicentric Cohort of Diabetic Patients.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Diabetes Mellitus
Insulin-Dependent
Keywords: Diabetes Mellitus
Insulin-Dependent
Genome-Wide Association Study
Environment-Wide Association Study
Predisposition
Complications
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Centre National de Génotypage
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2014-08-08
Enrollment: 20000
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
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.

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).

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).

Eligibility 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

Primary outcomes:
measure: Genetic and environmental risk factors of T1D predisposition
timeFrame: 10 years
Secondary outcomes:
measure: Genetic and environmental risk factors of T1D complications
timeFrame: 10 years
measure: Identify G and E factors influencing the process of remaining beta cells' destruction during the first 3 years after diagnosis
timeFrame: 5 years
measure: Identify G factors (pharmacogenomics) of the individual response to insulin using the effective insulin dose as a phenotype over a period of 2 years
timeFrame: 4 years
measure: Undertake a prospective research of G and E risk factors of "death in bed" syndrome in diabetic adolescents
timeFrame: 5 years
Other outcomes:
Locations:
city: Le Kremlin Bicêtre
country: France
facility: Inserm U986
Study officials:
affiliation: Inserm U986/ Pediatric endocrinology department of the Bicêtre hospital
name: Pierre BOUGNERES, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Balazard F, Le Fur S, Valtat S, Valleron AJ, Bougneres P; Isis-Diab collaborative group; Thevenieau D, Chatel CF, Desailloud R, Bony-Trifunovic H, Ducluzeau PH, Coutant R, Caudrelier S, Pambou A, Dubosclard E, Joubert F, Jan P, Marcoux E, Bertrand AM, Mignot B, Penformis A, Stuckens C, Piquemal R, Barat P, Rigalleau V, Stheneur C, Fournier S, Kerlan V, Metz C, Fargeot-Espaliat A, Reznic Y, Olivier F, Gueorguieva I, Monier A, Radet C, Gajdos V, Terral D, Vervel C, Bendifallah D, Signor CB, Dervaux D, Benmahammed A, Loeuille GA, Popelard F, Guillou A, Benhamou PY, Khoury J, Brossier JP, Bassil J, Clavel S, Le Luyer B, Bougneres P, Labay F, Guemas I, Weill J, Cappoen JP, Nadalon S, Lienhardt-Roussie A, Paoli A, Kerouedan C, Yollin E, Nicolino M, Simonin G, Cohen J, Atlan C, Tamboura A, Dubourg H, Pignol ML, Talon P, Jellimann S, Chaillous L, Baron S, Bortoluzzi MN, Baechler E, Salet R, Zelinsky-Gurung A, Dallavale F, Larger E, Laloi-Michelin M, Gautier JF, Guerin B, Oilleau L, Pantalone L, Lukas C, Guilhem I, De Kerdanet M, Wielickzo MC, Priou-Guesdon M, Richard O, Kurtz F, Laisney N, Ancelle D, Parlier G, Boniface C, Bockel DP, Dufillot D, Razafimahefa B, Gourdy P, Lecomte P, Pepin-Donat M, Combes-Moukhovsky ME, Zymmermann B, Raoulx M, Dumont AG. Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study. BMC Public Health. 2016 Sep 29;16(1):1021. doi: 10.1186/s12889-016-3690-9.