Coloration du stage :

L’activité principale sera l’analyse bioinformatiques des données

Cependant si tout se passe bien on pourra peut-être génotyper quelques variants communs sur une cohorte de réplication.

Laboratoire : TAGC
Lieu du stage : TAGC, Campus de Luminy
Nom de l'encadrant : Dr. Christophe Chevillard (CR1 INSERM) Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir.

Résumé :

Chagas disease (American trypanosomiasis) occurs mainly in poor, rural areas of Latin America. Approximately 120 million people are currently at risk of infection. The World Health Organization estimates that 300 000 new cases of Chagas disease occur every year. Approximately 20,000 deaths attributable to Chagas disease occur annually, typically due to myocarditis. In persons with chronic T. cruzi infection, mortality is primarily due to the rhythm disturbances and congestive heart failure that result from the chronic inflammatory cardiomyopathy (CCC) due to the persistence presence of parasites in the heart tissue. While the majority of the infected subjects (70%) remain in an asymptomatic, a significant proportion of those patients subsequently (30%) develop dilated cardiomyopathy with a fatal outcome.

The mechanisms underlying differential progression to CCC are still incompletely understood. Chagas disease remains a neglected disease, with no vaccine available so far and only very few anti-parasitic drugs proven efficient for treating the acute phase of the disease. No drug is available for chronic phase. Familial aggregation of CCC has been described, suggesting that there might be a genetic component to disease susceptibility. This is also supported by the fact that only one third of T. cruzi-infected individuals develop CCC. Moreover, previous case-control studies have already identified couples of genes associated to human susceptibility to Chronic Chagas disease Cardiomyopathies. We hypothesize here that genetic polymorphisms determining specific gene/protein expression profiles and activation of specific disease pathways are fundamental factors of the increased heart tissue damage is increased aggressiveness of CCC. So, we will conduct an international program that will identify these host genetic factors that predispose individuals to chronic disease.

Familial aggregation of CCC has been described, suggesting that there might be a genetic component to disease susceptibility. This is also supported by the fact that only one third of T. cruzi-infected individuals develop CCC. All the previous studies, done with the tools available in the 80’s, have confirmed the genetic control of human susceptibility to Chronic Chagas disease Cardiomyopathies. However, all these studies have serious limitations: A) The sizes of the study groups are limited. The statistical power, to detect real associations, is low and some described associations may result from type I errors. B) Some results were not confirmed on independent cohort. C) The number of tested SNPs in each candidate gene is limited and the functional polymorphisms are probably unidentified. D) Some studies mix populations from different countries. It is inducing heterogeneity that is not adapted to association studies. E) In some studies, the use, of not infected subjects as control group, is not relevant. We are not sure that these controls have been exposed to the parasite. F) These studies do not take in consideration the results obtained in other dilated cardiomyopathies.

To avoid these bottlenecks and to develop a genetic program lead to the identification of the host factors associate to the development of chronic chagas cardiomyopathy it is essential to have access to a very large population. The recruitment of this population is still ongoing but we had enrolled 1600 cases and 600 asymptomatic controls. GWAS was done with the CEA CNG. Data are available. The candidate will have to do the analysis, the imputation and the identification of candidate genes for each loci. Whole-exome sequencing has been widely applied in the identification of germline mutations underlying Mendelian disorders. Indeed. WES has been shown to lead to the spectacular identification of the molecular basis of rare Mendelian disorders in small numbers of unrelated affected individuals, or in a single affected individual when used in conjunction with Genome-wide linkage. In order to complement the GWAS approach, an exome sequencing strategy will be conducted on several nuclear families including multi severe cases and some asymptomatic subjects. The aim is to detect rare functional coding variants or copy number variations shared only by the severe chronic siblings (and not by the asymptomatic one) from the same nuclear family. Here again the data are available for analysis .