Chagas cardiomyopathy is still a leading cause of death in Latin American countries. It is also an emerging infectious disease in the US, estimated to have approximately 300,000 individuals with Chagas disease living within its borders. One of the most important and still unanswered questions in the disease is why only 30% of infected individuals develop chronic forms of end-stage cardiomyopathy. Here we hypothesize that genetic susceptibility is paramount and modulates end-stage disease development. For testing this hypothesis we will use a genetics approach based on the investigation of common genetic variation that may associate with disease development. In parallel, we will build the tools to also investigate whether rare genetic variations also have a role in disease susceptibility. This enterprise will be possible thanks to the team of several different Brazilian groups around this project. We will harness GWAS data already collected and generated by the REDS-II Study, the Bambui Study, and the Heart Institute Heart Failure Cohort Study. In addition, we will generate new large-scale genotype data from the SaMi-Trop Cohort. Taken together, our efforts will result on a more than 10-fold increase in the number of available individuals with Chagas disease that can be analyzed using a GWAS approach. Specifically, we propose to address this problem through the following specific aims: 1. Recruit 1,000 new individuals with the indeterminate form at the Montes Claros, MG region and conduct genome-wide genotyping experiments in 2,000 samples available from the SaMi-Trop cohort, the new indeterminate form group, and approximately 1,000 un-genotyped samples from the Brazilian Consortium for Genetics of Chagas Cardiomyopathy; 2. Conduct a meta-analysis of the different GWAS studies taking part in this initiative; 3. Ascertain and enroll T. cruzi infected individuals from the same nuclear families for the conduct of Chagas cardiomyopathy heritability and future sequencing studies.

Public Health Relevance

Chagas disease is caused by the parasite Trypanosoma cruzi and usually transmitted through vector insects in endemic areas. It is also a leading cause of heat failure and mortality and Latin America, is characterized by the late development of heart dilatation and severe forms of arrhythmias. It is not know who among infected individuals will develop heart disease later in their lives. In this study, we will test the hypothesis that genetic factors confer susceptibility to infected individuals for the development of heart disease. We will address this important question by conducting the largest-to-date genetic study in Chagas heart disease through the cooperation of several different Brazilian groups working in the field. Our enterprise will generate a more than 10-fold increase in available data and has the potential to unravel new genes associated with the condition. The knowledge generated through this project might be used to identify new prognostic markers and also to describe new targets that could be used for treatment of this deadly condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI098461-07
Application #
9476911
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Fundacao Faculdade de Medicina
Department
Type
DUNS #
902096528
City
Sao Paulo
State
Country
Brazil
Zip Code
05401-000
Chevillard, Christophe; Nunes, João Paulo Silva; Frade, Amanda Farage et al. (2018) Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy. Front Immunol 9:2791
Zrein, Maan; Granjon, Elodie; Gueyffier, Lucie et al. (2018) A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients. PLoS Negl Trop Dis 12:e0006226
Ferreira, Ludmila Rodrigues Pinto; Ferreira, Frederico Moraes; Nakaya, Helder Imoto et al. (2017) Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction. J Infect Dis 215:387-395
Capuani, Ligia; Bierrenbach, Ana Luiza; Pereira Alencar, Airlane et al. (2017) Mortality among blood donors seropositive and seronegative for Chagas disease (1996-2000) in São Paulo, Brazil: A death certificate linkage study. PLoS Negl Trop Dis 11:e0005542
Cardoso, Clareci Silva; Sabino, Ester Cerdeira; Oliveira, Claudia Di Lorenzo et al. (2016) Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile. BMJ Open 6:e011181
Ferreira, Ariela Mota; Sabino, Ester Cerdeira; de Oliveira, Lea Campos et al. (2016) Benznidazole Use among Patients with Chronic Chagas' Cardiomyopathy in an Endemic Region of Brazil. PLoS One 11:e0165950
Keating, S M; Deng, X; Fernandes, F et al. (2015) Inflammatory and cardiac biomarkers are differentially expressed in clinical stages of Chagas disease. Int J Cardiol 199:451-9
Carmo, Andre A L; Rocha, Manoel O C; Silva, Jose L P et al. (2015) Amiodarone and Trypanosoma cruzi parasitemia in patients with Chagas disease. Int J Cardiol 189:182-4
Capuani, Ligia; Bierrenbach, Ana Luiza; Abreu, Fatima et al. (2014) Accuracy of a probabilistic record-linkage methodology used to track blood donors in the Mortality Information System database. Cad Saude Publica 30:1623-32