AUTHOR=Gomes dos Santos Alexandra , Watanabe Elieser Hitoshi , Ferreira Daiane Tomomi , Oliveira Jamille , Nakanishi Érika Shimoda , Oliveira Claudia Silva , Bocchi Edimar , Novaes Cristina Terra Gallafrio , Cruz Fatima , Carvalho Noemia Barbosa , Sato Paula Keiko , Yamashiro-Kanashiro Edite Hatsumi , Pontillo Alessandra , de Freitas Vera Lucia Teixeira , Onuchic Luiz Fernando , Shikanai-Yasuda Maria Aparecida 

TITLE=A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.521409

DOI=10.3389/fimmu.2020.521409

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Chagas disease caused by <italic>Trypanosoma cruzi</italic> (<italic>T. cruzi</italic>) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between <italic>IL1B</italic>, <italic>IL6</italic>, <italic>IL17A</italic>, or <italic>IL18</italic> polymorphism profiles and cardiomyopathy or <italic>T. cruzi</italic> parasitemia, as well as the impact of HIV infection on cardiopathy.</p></sec><sec><title>Methods</title><p>Two hundred twenty-six patients and 90 control individuals were analyzed. <italic>IL1B</italic> rs1143627 T&gt;C, <italic>IL6</italic> rs1800795 C&gt;G, <italic>IL17A</italic> rs2275913 G&gt;A, <italic>IL18</italic> rs187238 C&gt;G, and <italic>IL18</italic> rs1946518 C&gt;A SNVs were analyzed by real-time PCR and <italic>T. cruzi</italic> parasitemia by PCR.</p></sec><sec><title>Results</title><p>Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The <italic>IL6</italic> rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24–0.86, P = 0.015). Original findings included associations between <italic>IL17A</italic> rs2275913 AA and <italic>IL18</italic> s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07–0.97, P = 0.044; and OR = 0.35, 95% CI 0.14–0.87, P = 0.023, respectively). <italic>IL18</italic> rs1946518 AA and <italic>IL1B</italic> rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06–0.68, P = 0.009; and OR = 0.48, 95% CI 0.24–0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) &lt;45% for <italic>IL18</italic> rs1946518 AA (OR = 0.22, 95% CI 0.05–0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23–0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06–0.39, P &lt; 0.001), and LVEF &lt; 45% (OR = 0.03, 95% CI 0.00–0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF &lt; 45% (OR = 0.20, 95% CI 0.09–0.47, P &lt; 0.001; and OR = 0.24, 95% CI 0.09–0.62, P = 0.004, respectively).</p></sec><sec><title>Conclusions</title><p>Our data support a protective role of <italic>IL17A</italic> AA, <italic>IL18</italic> AA, and <italic>IL1B</italic> TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the <italic>IL6</italic> CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.</p></sec>