Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease

Nogueira, L.; Frade, Amanda Farage; Ianni, Bárbara Maria; Laugier, Laurie; Pissetti, Cristina Wide; Cabantous, Stéphanie; Baron, Monique; Peixoto, Gisele de Lima; Borges, Ariana de Melo; Donadi, Eduardo Antônio; Marin-Neto, José Antônio; Schmidt, André; Dias, Fabrício C.; Saba, Bruno; Lin-Wang, Hui Tzu; Fragata, Abílio; Sampaio, Marcelo Ferraz; Hirata, Mário Hiroyuki; Buck, Paula; Mady, Charles; Filho, Martino Martinelli; Lensi, Mariana; Siqueira, Sérgio; Pereira, Alexandre C.; Rodrigues, Virmondés; Kalil, Jorge; Chevillard, Christophe; Cunha-Neto, Edécio

doi:10.1016/j.cyto.2015.01.037

Cited by 22 publications

(24 citation statements)

References 53 publications

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“…On the other hand, a previous study showed that IL18 rs2043055 may modulate Chagas disease severity in a Brazilian population [ 15 ]. In our study we were not able to find an association of any of the analyzed IL18 SNPs (including this one) with the severity of Chagas disease.…”

Section: Discussionmentioning

confidence: 99%

“…In order to comprehensively analyze the possible role of IL18 on the genetic susceptibility to Chagas disease, a total of six single-nucleotide polymorphisms (SNP) within the locus were selected for genotyping following a combined candidate gene/tagging strategy. These include: 1) two promoter variants (rs187238 and rs1946518) that have been reported to affect gene expression [ 24 – 27 ]; 2) one intronic variant (rs2043055) previously implicated in Chagas disease outcome in a Brazilian population [ 15 ]; 3) an additional promoter variant (rs360719) that has been described to interact with the transcription factor OCT-1 [ 28 ]; and 4) two intronic tag SNPs (rs5744258 and rs360722) covering the remaining variability of the IL18 gene. These latter variants were selected with the software Haploview V4.2 [ 29 ] on the basis of both pairwise tagging (r 2 >0.80) and minor allele frequencies >0.1, using Colombian-Medellín (CLM) genotype data from the 1000 genomes phase III project ( http://www.1000genomes.org ) [ 30 ], encompassing the coding and promoter regions of IL18 and considering the four previously selected candidate variants.…”

Section: Methodsmentioning

confidence: 99%

“…Consistent with the above, previous studies have suggested a genetic influence of both IFNG and IL18 gene variants in the susceptibility to infection by T . cruzi and Chagas cardiomyopathy, respectively [ 9 , 15 ], adding additional evidences to the high relevance that this pathway may have in Chagas disease development.…”

Section: Introductionmentioning

confidence: 99%

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IL18 Gene Variants Influence the Susceptibility to Chagas Disease

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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IL18 Gene Variants Influence the Susceptibility to Chagas Disease

et al. 2016

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“…4 As such, cytokine and cytokine receptor genes have been studied in order to find any association between genes and the susceptibility and/or development of cardiomyopathy in patients from different endemic countries. 5 Polymorphisms in genes encoding proinflammatory cytokines such as TNF-α, 6,7 lymphotoxin-α, 8 and IL18 9 have been found to be associated with chronic Chagas cardiomyopathy. Similarly, polymorphisms in genes encoding regulatory cytokines such as IL10, 10 chemokines CCL2, CXCL9 and CXCL10, the chemokine receptor CCR5 11,12 have also been found to be associated with cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the role of IL17A gene variants in Chagas disease

et al. 2015

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Human host genetic factors have been suggested to be determinants of the prevalence and clinical forms of Chagas disease. In this regard, IL-17A is believed to control parasitemia and protect against heart disease. In this work, we assessed whether IL17A gene polymorphisms are related to infection and/or development of the cardiac form of Chagas disease by genotyping for five IL17A SNPs (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) in 1171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n=595), seropositive asymptomatic (n=175) and chronic Chagas cardiomyopathy (n=401). Our results showed that SNP rs8193036, which is located upstream of the coding region of the gene, was slightly associated with protection against T. cruzi infection (P=0.0170, P(FDR)=0.0851, odds ratio (OR)=0.80, confidence interval (CI)=0.66-0.96) and associated with protection against the development of cardiomyopathy (P=0.0065, P(FDR)=0.0324, OR=0.75, CI=0.60-0.92). This finding suggests that this IL17A polymorphism could be associated with Trypanosoma cruzi infection and the development of chronic cardiomyopathy due to differential expression of cytokine IL-17A.

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“…Other studies that highlight the role that protozoan parasites had in shaping the genetics of human populations were recently reviewed [129]. These studies suggest that quantitative trait loci and/or human polymorphisms play a role in genetic susceptibility to parasite burden and/or associated pathology for different pathogens of human [130][131][132][133] and livestock [134,135]. These types of investigations, however, require large cohorts of individuals (patients or animals), generate large sequence data sets, and usually lack causal conclusions.…”

Section: Host Genetics: the Neglected Side Of The Host-pathogen Intermentioning

confidence: 97%