<i>IL18</i> Gene Variants Influence the Susceptibility to Chagas Disease

<div><p>Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan <i>Trypanosoma cruzi</i>. 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 (<i>IL18</i>) encodes a proinflammatory cytokine that has been proposed to be involved in controlling <i>T</i>. <i>cruzi</i> infection. In this study, we analyzed the possible role of six <i>IL18</i> gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by <i>T</i>. <i>cruzi</i> 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 <i>T</i>. <i>cruzi</i> 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 <i>IL18</i> 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 <i>IL18</i> gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of <i>IL18</i> is directly involved in the susceptibility to infection by <i>T</i>. <i>cruzi</i>, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.</p>