Clinical trial NCT02425410: Analysis of Viral Infections' Exposition Preceding the Type 1 Diabetes (T1D) Diagnostic in Children of the Isis-Diab Cohort. Search for Explanations of of the Disease's Early Onset
Official title: Analysis of Viral Infections' Exposition Preceding the Type 1 Diabetes (T1D) Diagnostic in Children of the Isis-Diab Cohort. Search for Explanations of of the Disease's Early Onset
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Diabetes Mellitus
Insulin-Dependent
Keywords: Diabetes Mellitus
Insulin-Dependent
Virus Diseases
Questionnaires
Risk assessment
Genome-Wide Association Study
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: 2015-04-24
Enrollment: 2000
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients of the Isis-Diab cohort, i.e. T1D patients aged more than 6 months, already sampled for genetic analysis.

Brief summary: The purpose of this study is to investigate viral factors determining the early onset of T1D. Thanks to the quantification of viral exposures of T1D patients before the disease onset with questionnaires and environmental databases analyses, and through whole genome association studies of these patients, investigators could attempt to identify gene-virus interactions determining the age of T1D onset.

Detailed description: The "hygiene hypothesis", which has been proposed to explain the observed increase of the incidence of T1D, relies on experimental evidence acquired in mouse models. However, epidemiological data are still lacking to validate this hypothesis in man. This is critical, because -in opposition with the hygiene hypothesis- there are many reasons to believe that, at contrary, certain virus can trigger the disease.

Genetic predisposition to a severe infection form (particularly primary infection) was demonstrated for several infectious diseases (Casanova JL, Science 317:617-619, 2007; Casanova JL, EMBO J 26:915-922, 2007). It usually corresponds to deficiencies in genes involved in the host's immune response, the transmission of which being Mendelian. Genetic factors affect the ability of enteroviruses and other viruses to damage beta cells and to induce diabetes. Recently, Nejentsev et al have demonstrated a link between enteroviruses and diabetes genes: they have indeed identified 4 rare IFIH1 polymorphisms that reduce the T1D risk. However, this gene encodes an enzyme recognizing the DNA enterovirus, causing immunity activation; mutations inhibit gene activation. Except one study on HIV-1, there is to our knowledge no genome wide association studies (GWAS) in humans on the role of host's genetic polymorphisms in the risk of infection, clinical expression, duration of viral shedding, or response to therapy or to anti-viral vaccines.

We relied on our cohort of T1D children (Isis-Diab) to investigate the possible relation between viral exposures, genetic polymorphisms, and subsequent T1D.

The search for viral factors responsible for the increased T1D prevalence in youth children is difficult to implement. The absence or scarcity of infections is difficult to assess robustly at the individual level. The analysis of digestive, ENT or blood samples in the search for viruses themselves can only be done at T1D diagnosis and is therefore unlikely to be positive several years after the causal infection. It is not possible to reconstitute retrospectively viral events, which an individual has been exposed between birth and date of diabetes diagnosis. That is why our project proposes to use a proxy of viral infections crossed by a child, quantifying viral exposures to which he was submitted before the T1D diagnosis. We focused on early childhood's viral infections that may interfere with early forms of T1D. We combine 2 data sources:

* The geolocation of the child's address will locate places where he lives. Spatio-temporal data from Sentinel Network, collected since 1984, will provide access on the following viral exposures: seasonal influenza, viral diarrhea (mostly enteroviral), mumps, measles, chickenpox. If the defect of our approach is that it does not see real viral infections experienced by children, but only the level of exposure to which they were exposed according to their address, the advantage is an objective spatio-temporal description of virus epidemics around children, making it more or less likely infection of these. Only France has such Sentinel data.
* Vaccination (including MMR) and information on infectious past of children will be collected from data recorded in his book health. We will focus on the mother's pregnancy and the child between birth and 2 years of age.

Environmental data from these 2 sources will be crossed with already available genetic data from GWAS to identify gene-virus associations potentially determining age of T1D onset. This "high dimensionality" analysis will be addressed with "machine learning" programs.

If avoidable risks are identified, it would be possible to think to design clinical trials for prevention of the identified forms of T1D.

Eligibility criteria: Inclusion Criteria:

* Type 1 diabetic patients included in the Isis-Diab cohort
* Patients with available genetic data (GWAS)

Exclusion Criteria:

* Patient refusal (or parents) to participate in the study.

Primary outcomes:
measure: Occurrence of viral events before T1D diagnosis
timeFrame: From birth to 2 years
measure: Delay between viral events and T1D diagnosis
timeFrame: From birth to 2 years
Secondary outcomes:
measure: Age at T1D diagnosis as a quantitative trait
timeFrame: From birth to 2 years
Other outcomes:
Locations:
city: Le Kremlin Bicêtre
country: France
facility: Inserm U986
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Alain-Jacques Valleron, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inserm U986 / Pediatric endocrinology department of the Bicêtre Hospital (AP-HP)
name: Pierre Bougnères, MD, PhD
role: STUDY_DIRECTOR
References: