A specific IL6 polymorphic genotype modulates the risk of T. cruzi parasitemia while IL18, IL17A and IL1B variant profiles and HIV infection protect against cardiomyopathy in Chagas disease
Watanabe, Elieser et al. (2021), A specific IL6 polymorphic genotype modulates the risk of T. cruzi parasitemia while IL18, IL17A and IL1B variant profiles and HIV infection protect against cardiomyopathy in Chagas disease, Dryad, Dataset, https://doi.org/10.5061/dryad.wstqjq2hn
Background: Chagas disease caused by Trypanosoma cruzi (T. cruzi) 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 IL1B, IL6, IL17A or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy.
Methods: 206 patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR.
Results: Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 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 IL17A rs2275913 AA and IL18 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). IL18 rs1946518 AA and IL1B 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) <45% for IL18 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<0.001) and LVEF<45% (OR=0.03, 95% CI 0.00‐0.25, P=0.001). Digestive involvement was negatively associated with NYHA ≥2 and LVEF<45% (OR=0.20, 95% CI 0.09‐0.47, P<0.001; and OR=0.24, 95% CI 0.09-0.62, P=0.004, respectively).
Conclusions: Our data support a protective role of IL17A AA, IL18 AA and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 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 HAART, attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.
Our cohort included 206 patients with Chagas disease: 78 from the Heart Institute of Hospital das Clínicas da Faculdade de Medicina, University of São Paulo (HCFMUSP), and 129 from the Infectious Diseases Division of HCFMUSP, 49 of whom with HIV co-infection. These 49 cases were followed at Serviço de Extensão e Atendimento aos Pacientes com Infecção por HIV/Aids of the same Division. All participants were adults. The diagnosis of trypanosomiasis was based on the 2nd Brazilian Guidelines for Chagas Diseases (1). Two positive tests of the following ones, therefore, were used to establish the diagnosis: ELISA - enzyme linked immunosorbent assay, indirect immunofluorescence, and hemagglutination (39). All patients from the Infectious Diseases Division with positive epidemiology were sent to the HIV/Aids Clinic, where HIV infection was confirmed by ELISA and immunoblot (31). Patients from the Heart Institute were tested for HIV as previously described (31). When included in the current protocol, 26 of the 49 HIV patients were not on regular HAART therapy or had therapeutic failure due to antiretroviral resistance (3 patients). In 23 of them, the median viral load was 14,000 (2,618-100,000) DNA viral copies/µL while the median CD4 count was 340 (93-510) cells/mm3. Data from 23 patients under HAART for 1 to >5 years showed a median viral load of 0.0 (0.0-0.0) DNA viral copies/ µL. In these 23 patients, the median CD4 count was 631 (439-715) cells/ mm3.
The patients underwent electrocardiography, echocardiography, and thorax, esophagus, and colon radiological examinations, being then classified within one of the clinical forms of Chagas disease (1). Individuals without signs and symptoms and with no alteration in the mentioned tests were classified as having the indeterminate form (n=51), patients with abnormalities suggestive of Chagas disease on electrocardiography or on dynamic electrocardiography and without digestive involvement as with the cardiac form (n=96), the cases with abnormal findings on esophagus and/or colon without Chagas cardiac manifestation as presenting the digestive form (n=32). Twenty seven patients presented both digestive and cardiac alterations, constituting the cardiodigestive group. Cardiac involvement was detected in 123 patients (cardiac and cardiac/digestive forms) while heart disease was not identified in 83 patients, a group composed of individuals with the indeterminate and digestive forms.
Patients with cardiomyopathy were evaluated for heart failure according to the New York Heart Association (NYHA) classification (40) and placed in one of two groups based on the left ventricular ejection fraction (LVEF) yielded by echocardiography: ≥45% or <45%.
The dataset is in xlsx format. It contains the patients demographics, clinical, laboratorial and echocardiogram data and the genotypes for IL1B, IL6, IL17A and IL18 polymorphisms.
São Paulo Research Foundation, Award: #12/50273-0
São Paulo Research Foundation, Award: #12/50273-0