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).

Genetic susceptibility to type 1 diabetes in human

Responsible: Cécile Julier

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β cells. Currently, three genes have been confirmed to play a role in the susceptibility to T1D, HLA, insulin (INS) and PTPN22. Our research focuses principally on the identification of the other susceptibility genes, some of which we mapped earlier. 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, including the genetic study of monogenic subtypes of T1D (atypical and syndromic forms of diabetes). In addition, we participate in an international consortium on T1D (T1DGC), whose aim is to organize genetic studies of T1D on a large scale.

Genetics of monogenic subtypes of diabetes

Responsable : Cécile Julier

In addition to the "typical" type 1 diabetes, a multifactorial disease, rare forms of atypical diabetes with monogenic inheritance have been described. The identification of these genes provides a better understanding of the development and function of the pancreatic β cell. In addition, these genes represent good candidates for playing a role in the susceptibility to frequent diabetes (type 1 and type 2). We previously identified several genes whose mutations are responsible for rare syndromes: 1) EIF2AK3 (translation initiation factor 2-α kinase 3) in Wolcott-Rallison syndrome, a very rare autosomal recessive disorder, characterized by the association of a neonatal permanent insulin-dependent diabetes and epiphyseal dysplasia (Delépine et al., Nature Genetics 25: 406-409, 2000 ; Senée et al, Diabetes 53:1876-1883, 2004); 2) PTHR1 (PTH/PTH-rP receptor 1) in Eiken syndrome, another very rare form of chondrodysplasia, associated with T1D in one of the four patients studied (Duchatelet, Hum Mol Genet, 14:1-5, 2004) ; 3) One gene responsible for another type of neonatal syndromic diabetes (V. Senée, unpublished results).

Genetic studies of susceptibility to infectious diseases: malaria and dengue

Responsible: Anavaj Sakuntabhai, Cécile Julier

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, using a candidate gene approach in case/control populations for severe dengue. We have assembled a large cohort of more that 600 cases and controls from Thailand (collaboration with Mahidol University). We recently showed that a promoter variant in the DC-SIGN gene (CD209), an attachment molecule for dengue virus, is involved in the severity of dengue disease (Sakuntabhai et al., Nature Genet 37: 507-513, 2005). We are currently studying other candidate genes, using the same approach.

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.

Keywords: infectious diseases, autoimmune diseases, malaria, dengue, type 1 diabetes, genetic susceptibility, human genetics

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