Unit: Genetic Predisposition to Infectious Diseases

Director: Cécile Julier

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, and then confirmed (P-value=7x10-7) is currently the only one (in addition to HLA and INS) that has been statistically confirmed by genetic linkage studies (ECIGS, Am J Hum Genet 69 : 1301-1313, 2001). 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 atypical diabetes syndromes

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 (Delépine et al., Nature Genetics 25: 406-409, 2000). 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: one case (onset at 18 months) was the patient with no EIF2AK3 involvement; the other case (onset at 30 months) was a patient with EIF2AK3, that had some weak residual activity in some functional assays (Senée et al., Diabetes 53:1876-1883, 2004). 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.

Eiken syndrome is another very rare syndrome with a characteristic epiphyseal dysplasia, that has been described in a single family. By genetic study of the original and single family described with this syndrome (6 available members), we identified the PTH/PTH-rP receptor (PTHR1) gene as the gene responsible for this syndrome (Duchatelet et al. Hum Mol Genet, 14:1-5, 2004). One of the patients affected with this syndrome developed T1D, suggesting that this gene may also predispose to T1D.

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


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