AUTHOR=Frade-Barros Amanda Farage , Ianni Barbara Maria , Cabantous Sandrine , Pissetti Cristina Wide , Saba Bruno , Lin-Wang Hui Tzu , Buck Paula , Marin-Neto José Antonio , Schmidt André , Dias Fabrício , Hirata Mario Hiroyuki , Sampaio Marcelo , Fragata Abílio , Pereira Alexandre Costa , Donadi Eduardo , Rodrigues Virmondes , Kalil Jorge , Chevillard Christophe , Cunha-Neto Edecio 

TITLE=Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01386

DOI=10.3389/fimmu.2020.01386

ISSN=1664-3224

ABSTRACT=Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN- and IFN--producing Th1-type T cells are increased in peripheral blood  and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN--producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN- production by Th1-type T cells may be a key event for progression towards CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. Methods We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed  35 Tag SNPs designed to represent all the genetic information contained in the IL12B, IL10, IFNG and IL4 genes. Results We found 4 IL12 SNPs (rs2546893, rs919766, rs1003199, rs11574790) and 2 IL10 SNPs (rs3024496 and rs18008) to be significantly associated with the ASY group. After multivariate analysis, two IL12B SNPs (rs2546893, rs919766) and one in IL10 (rs3024496) remained associated. No association was found for the studied IFNG or IL4 SNPs.  Conclusions Our data show that novel polymorphisms affecting IL12B and IL10, but not  IFNG or IL4 genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled.