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 (ISIS-VIRUS)

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Anticipated)

2000

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

No

Genders Eligible for Study

All

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.

Description

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.

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

  • Observational Models: Case-Only
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Isis-Virus
T1D patients of the Isis-Diab cohort with genetic data (GWAS) and specific environmental data on viral events during childhood
Other: Collect of data on viral environment of T1D patients
Questionnaires on viral events 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 Genotypage)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Occurrence of viral events before T1D diagnosis
Time Frame: From birth to 2 years
From birth to 2 years
Delay between viral events and T1D diagnosis
Time Frame: From birth to 2 years
From birth to 2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Age at T1D diagnosis as a quantitative trait
Time Frame: From birth to 2 years
From birth to 2 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: Alain-Jacques Valleron, PhD, Institut National de la Santé Et de la Recherche Médicale, France
  • Study Director: Pierre Bougnères, MD, PhD, Inserm U986 / Pediatric endocrinology department of the Bicêtre Hospital (AP-HP)

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.

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

March 1, 2010

Primary Completion (Anticipated)

December 1, 2017

Study Completion (Anticipated)

June 1, 2018

Study Registration Dates

First Submitted

August 7, 2014

First Submitted That Met QC Criteria

April 23, 2015

First Posted (Estimate)

April 24, 2015

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 10061

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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