Abstract
Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.
Highlights
Host genetic factors have been suggested to play an important role in the susceptibility to human infectious diseases [1]
Chagas disease is a parasitic disorder caused by the infection with the protozoan Trypanosoma cruzi
We investigated in an endemic region of Colombia whether the Interleukin 18 (IL18) gene, which is involved in the immune response to intracellular pathogens like T. cruzi, is related to a higher susceptibility to infection or disease severity
Summary
Host genetic factors have been suggested to play an important role in the susceptibility to human infectious diseases [1]. An example of such conditions is Chagas disease, which is caused by infection of the protozoan Trypanosoma cruzi. Several studies have investigated the possible role of gene polymorphisms in the predisposition to T. cruzi infection and/or chronic Chagas cardiomyopathy in patients from endemic countries, reporting promising results [5,6,7,8,9,10,11,12,13,14,15,16,17]
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