|Genetic Predisposition to Infectious Diseases|
|Director : Cécile Julier (email@example.com)|
The main aim of our studies is the mapping, identification and study of genes involved in the susceptibility/resistance to 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.
Genetic susceptibility to type 1 diabetes in human
Responsible: Cécile Julier
Based on our previous studies performed in French, North-American and Scandinavian families with at least two siblings affected with T1D, we were able to confirm linkage of T1D to 11q13 (IDDM4 locus) and 6q21 (IDD15 locus) regions, with stringent statistical criteria; in particular, the IDDM15 locus , which we had initially detected, is currently the only one (in addition to HLA and INS) which has been statistically confirmed by genetic linkage studies (statistical P-value: 7x10-7). These regions, and new ones that we identified in our last genome-wide scan in Scandinavian families, are the focus of detailed genetic studies in our laboratory, in order to identify the responsible genes and variants. These studies are mostly based on systematic association screening in these regions, with complementary approaches: (1) studies of consanguineous T1D families and monogenic or oligogenic subtypes, (2) association studies in sub-groups defined according to phenotypic and genetic criteria. In addition, we participate in an international consortium on T1D (T1DGC), whose aim is to organize genetic studies of T1D on a large scale.
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-α kinase 3), in which we identified mutations segregating with the disorder in the two families studied. We have now studied 12 families (18 patients) with this syndrome, and identified EIF2AK3 mutations in 11 of these. In one of these families, we could exclude EIF2AK3 involvement, suggesting genetic heterogeneity in this syndrome. In this syndrome, diabetes is generally neonatal or occurring in the early childhood (< 6 months), however two of these patients had onset at 18 and 30 months. In one case (18 months), it was the patient with no EIF2AK3 involvement; in the other case, we found some weak residual activity of EIF2AK3. These results suggest that variants of this gene may be associated to less extreme phenotypes of this disease. This gene represents a potential candidate for frequent forms of diabetes (type 1 and type 2). Interestingly, the region of this gene (2p12) shows linkage to T1D in Scandinavian families (see above), which strengthens our hypothesis that this gene may be involved in the susceptibility to T1D, an hypothesis that we are currently testing.
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 and Thailand. Many epidemiological, clinical and immunological studies have been performed in the Senegalese families during the last 10 years (Pasteur Institutes of Paris and Dakar, IRD). In these families, we found evidence for the implication of genetic factors in several relevant phenotypes. We performed a genome-wide scan in these families (collaboration with the Centre National de Génotypage, Evry) with complementary studies of candidate genes and regions, in order to map and identify these genetic factors. A similar study is in progress in Thai families.
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, or genes involved in the variability of the clinical features in these severe forms, using a "candidate genes" approach in a large case/control population for severe forms of dengue, which has been collected in Thailand (collaborations with several groups from Mahidol University).
Keywords: infectious diseases, autoimmune diseases, malaria, dengue, type 1 diabetes, genetic susceptibility, human genetics
|Publications 2003 of the unit on Pasteur's references database|
|Office staff||Researchers||Scientific trainees||Other personnel|
|Roux, Cécile, (firstname.lastname@example.org)||Julier, Cécile, INSERM, (DR1, email@example.com)
Sakuntabhai, Anavaj, Institut Pasteur, (chargé de recherche, firstname.lastname@example.org)
|Peerapittayamongkol, Chayanon, post-doc, poste vert INSERM
Senée, Valérie, post-doc, bourse JDRF/FRM/INSERM
Ndiaye, Rokhaya, étudiante thèse
Ghandil, Pegah, étudiante thèse
Duchatelet, Sabine, étudiante thèse
Kalayanarooj, Sita, étudiante thèse (Thaïlande)
Turbpaiboon, Chairat, étudiant thèse (Thaïlande)
Quintin, Thibaut, étudiant DEA
|Casadémont, Isabelle, (Ingénieur de Recherche, Institut Pasteur, email@example.com)
Lavergne, Anne, (Ingénieur de Recherche, Institut Pasteur, firstname.lastname@example.org)
Blanc, Hervé, (Technicien Supérieur, Institut Pasteur, email@example.com)
Roux, Cécile, (Secrétaire, Institut Pasteur, firstname.lastname@example.org)