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  Director : Julier, Cécile (cjulier@pasteur.fr)


  abstract

 

The main aim of our studies is the mapping, identification and study of susceptibility genes for multifactorial diseases: one autoimmune disease, type 1 diabetes (T1D), and infectious diseases, malaria and dengue. The genetic approach, common to these two types of diseases, is based on familial studies as well as population-based studies (case/control). For T1D, two susceptibility genes are already known, HLA and insulin, and our research is focusing on the identification of the other genes, whose chromosomal localisation we have been able to confirm in some cases.



  report

cale

Genetic susceptibility to type 1 diabetes in human. Responsible: Cécile Julier

Our research on type I diabetes is currently focusing on two main areas: (1) Search for the susceptibility genes corresponding to loci IDDM4 (11q13) and IDDM15 (6q21), for which we previously established and confirmed the localisation of genes, based on stringent statistical criteria. These studies are based on fine association mapping, in order to precisely define the position of the responsible genes, and identify them and the responsible variants. (2) Following our genome wide study of T1D in 421 Scandinavian families with at least two affected children (European collaborative project ECIGS), we were able to confirm linkage to HLA (6p21), insulin (11p15, in TDT studies), and IDDM15 (6q21). We also detected potential linkage in three other regions (LOD score values >2.0), which had not been detected in other studies, on chromosomes 2, 5 and 16. Analyses under HLA or INS susceptibility stratification showed increased evidence of linkage, with LOD>3.0 in several instances. We are currently pursuing the search for susceptibility genes corresponding to these new loci.

Wolcott-Rallison syndrome and EIF2AK3 gene. Responsible: Cécile Julier

Wolcott-Rallison syndrome is a very rare autosomal recessive disorder, characterized by the association of a neonatal permanent insulin-dependent diabetes and epiphyseal dysplasia. From the study of two consanguineous families, with a total of 10 individuals, 5 of which were affected children, and 1 was a healthy child, we were able to identify the gene mutated in this disorder. This is EIF2AK3 (translation initiation factor 2-a kinase 3), in which we identified mutations segregating with the disorder in the two families studied. This gene represents a potential candidate for frequent forms of diabetes (type 1 and type 2). Interestingly, the position of the T1D susceptibility locus that we mapped on chromosome 2 in Scandinavian families (see above) corresponds to that of EIF2AK3, which reinforces our hypothesis that this gene may be involved in the susceptibility to type I diabetes.

Susceptibility to autoimmune diabetes in the mouse. Responsible: Evie Melanitou

Genetic studies of autoimmune diabetes conducted in human and mouse have identified a minority of syntenic susceptibility loci. These syntenies may be fortuitous, as a result of the large number of confirmed or putative susceptibility loci mapped in both species. These may also in some cases represent genuine homologous genes involved in diabetes susceptibility in both species. This is the hypothesis that we have made for a locus on mouse chromosome 6, which appears linked to autoimmune diabetes as well as to other autoimmune diseases, and which is syntenic to the human 2p12 region where EIF2AK3 is located. We are currently testing this gene in the corresponding animal models.

Genetic studies of susceptibility to infectious diseases: malaria and dengue. Responsible: Anavaj Sakuntabhai, Cécile Julier

Several genes have been implicated in the resistance to severe malaria. Our project is to identify genes involved in the variability of phenotypes related to malaria infection, and to study the mechanisms involved. These studies are based on the analysis of families located in areas of endemic malaria: Senegal, Burkina-Faso (collaboration with F. Fumous, Marseille) and Thailand. Many epidemiologic, clinical and immunological studies have been performed in the Senegalese families during the last 10 years (Pasteur Institutes of Paris and Dakar, IRD). We dispose of the DNA and malaria phenotypes of 900 people, and have established the genealogic trees of the population (two villages). These trees show major founder effects, which should increase the power of genetic studies. We are performing genome-wide studies (collaboration with Mark Lathrop, Centre National de Génotypage, Evry) and candidate genes and candidate regions studies in the Senegalese and Burkinabe families, and later in the Thai families, with the aim to map genes involved in the response to malaria infection, and in the differential susceptibility to P. Falciparun and P. vivax, which coexist in Thailand. Our preliminary analyses showed that the heterozygous status for HbS variant is associated with a reduction of the number of malaria attacks, which therefore validates our approach in these villages.

Dengue virus is endemic in several tropical countries, particularly in South-East Asia, where the infection results in 1-2% of cases in severe forms, hemorrhagic or shock, which can lead to death. Our project is to identify susceptibility genes for these severe cases, using a "candidate genes" approach in case/control populations for severe forms of dengue, which are being collected in Thailand.



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
 

Lozano, Liliane, llozano@pasteur.fr

Julier, Cécile, INSERM, DR2, cjulier@pasteur.fr

Sakuntabhai, Anavaj, Institut Pasteur, researcher, anavaj@pasteur.fr

Melanitou, Evdokia, Institut Pasteur, researcher, eviemel@pasteur.fr

Senée, Valérie, PhD student

Ndiaye, Rokhaya, PhD student

Ghandil, Pegah, PhD student

Duchatelet, Sabine, DEA student

Samadi, Zahra, researcher

Peerapittayamongkol, Chayanon, post-doc fellow

Casadémont, Isabelle, Institut Pasteur, Engineer

Joffret, Marie-Line, Institut Pasteur, Engineer

Blanc, Hervé, Institut Pasteur, Technician


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