CV Science

christophe chevillard Identification of a predictive/prognostic genetic signature in Chagas Cardiomyopathy: A systems biology approach

Course and current status

Master Degree in Enzymology (1991) and PhD in Microbiology in 1994, both from the university Aix-Marseille II. He has a postdoctoral position in the Roy Riblet’s laboratory working on the physical map of the C57BL mouse Igh locus. He has joined the Alain Dessein’s laboratory (Marseille) 10 years ago as principal investigator. Since 1997, he focused his research on the identification and the characterization of genetic factors that control human susceptibility to infection and severe disease in Schistosomiasis.

Indeed infection levels are under the control of a major locus that mapped to the 5q31-q33 region. In collaboration with the Pr. O Doumbo (Department of Epidemiology and Parasitic Diseases, Bamako, Mali), we had shown that infection levels are under a genetic control that involved at least IL13 and STAT6 genes. Moreover, since these studies we developed some strategies based on linkage disequilibrium tests that permit to detect a haplotype of susceptibility in IL13 gene. Concerning the control of human susceptibility to severe diseases, liver fibrosis are also under the control of a major locus that mapped to the 6q22-q23 region. The UMR906 laboratory and the Hunan Institute for Parasitic Diseases (Yueyang, China) have characterized two Chinese populations living in an endemic area for S. Japonicum. A case control studies, based on the study of the CTGF gene, indicated that several polymorphisms around this gene are associated to a highest risk to develop severe fibrosis. The associated polymorphisms are located either in the 3’ region of this candidate gene or in the promoter region. In collaboration with the Institute of Nuclear medicine (Wad Medani, Sudan), we had confirmed these associations in Sudan in a population living in an endemic area for S. mansoni. Same confirmation was obtained on a population leaving in an endemic area in Brazil (collaboration with the faculdae de Medicina do Triangulo Mineiro (Uberaba, Brazil) and universidade Federal de Pernambucco (Pernambucco, Brazil). Some functional studies have allowed the identification the functional variants. Based on HapMap data, we were able to shown that these variants are no correlated to other variants localized in the same chromosomal region.

Since 2010, in the same laboratory, He is developing in collaboration with several groups some programs in order to identify human susceptibility genes for chronic Chagas cardiomyopathy. Chagas disease occurs exclusively in the Americas, particularly in poor, rural areas of Mexico, Central America and South America. Approximately 20,000 deaths attributable to Chagas disease occur annually, typically due to myocarditis. Mechanisms underlying differential progression to CCC are still incompletely understood. Familial aggregation of CCC has been described, suggesting that there might be a genetic component to disease susceptibility. The outcome of infection in a particular individual is the result of a set of complex interactions among environmental, social factors, the genetic of the parasite strains and the host genetic background. Our main aim is to identify the host genetic factors that predispose individuals to chronic disease. This analysis will be performed on a very large Brazilian population (the largest described so far). This program is including genetic, proteomic, epigenetic transcriptomic approaches. A similar program is also in progress to identify susceptibility genes involved in severe demantia.

Scientific summary

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects ca. 15 million people. About 30o/o of Chagas disease patients develop Chronic Chagas disease cardiomyopathy (CGC), an particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic (ASY;60o/o). Clinical severity in Chagas disease is correlated with the occurrence of myocarditis, and survival is worse than for that of non-inflammatory cardiomyopathy. CCC heart lesions present a Th1 T cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Chagas thus remains a neglected disease, with no vaccines or anti-parasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Development of effective drugs for CCC is hampered by the limited knowledge of Ils pathogenesis. Familial aggregation of CGC cases, as well as the fac! that only 30% of infected patients develop CCC, suggest there might be a genetic component to disease susceptibility. Moreover, previous casecontrol studies have identified some genes associated ta human susceptibility to CGC.The outcome of Chagas disease is ultimately defined in the patients' hearts, a consequence of inflammation and myocardial tissue response. We th us hypothesize that expression of many pathogenetically relevant genes and proteins in the myocardial tissue of CCC patients is controlled by genetic polymorphisms. The corollary is that it may be possible to establish a hast genetic signature with prognostic value based on such polymorphie genes. For that matter, we will use a systems biology approach ta identify 1) genes/proteins that are differentially expressed in CCC myocardium 2) functional polymorphisms that may contrai their expression or function. This application is based on two independent aims. First, we will identify differentially expressed genes and proteins in the already available fresh-frozen CGC heart samples. Proteomic and transcriptomic analysis of such samples will allow identification of differentially expressed genes. Methylation analysis and miRNA profiling will be performed ta "filter out" genes regulated by these two mechanisms (the characterization of such genes could be an application by itself). The resulting list will be targeted by the genetic approaches. The partners have previously engaged ta enroll a large Brazilian chagasic population. Sa far we have DNA samples for 1200 CCC and 600 ASY patients; our goal is to increase numbers to gel a main cohort (700 CCC/400 ASY control subjects) and an independent replication cohort (300 CGC and 300 ASY subjects).The second objective is the identification of genetic variants associated ta disease. The first approach is a case-contrai study based on common SNPs tram the stongest candidate genes identified in Aim 1, where common Tag single nucleotide polymorphisms (SNP) will be genotyped using the Sequenom technology. We will also characterize multicase nuclear familias (including two CGC and one ASY sibs) by exome sequencing, ta identify rare functional variants shared only by the cases but not by the internai contrais (ASY subjects); the partners have access to the families at an endemic area. This approach will benefit tram the data analysis expertise of the second French partner. Univariate and multivariate analyses will be conducted to identify associated markers. Functional analyses will assess whether SNPs affect gene expression, function or protein structure. The identification of these marker sets will have a combined prognostic value for disease progression at the individual patient level, allowing close follow up and early treatment of those carrying high-risk genetic signatures. Moreover, this study will provide significant information ta decipher mechanisms underlying chronic disease progression and ta identify future therapeutic targets.