IL6 -174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil

L. Castellucci, E. Menezes, J. Oliveira, A. Magalhaes, L.H. Guimaraes, M. Lessa, S. Ribeiro, J. Reale, E.F. Noronha, M.E. Wilson, P. Duggal, T.H. Beaty, S. Jeronimo, S.E. Jamieson, A. Bales, Jenefer Blackwell, A.R. De Jesus, E.M. Carvalho

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Abstract

BackgroundMucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor–α and interferon-γ responses and tissue destruction. ML follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis infection. Interleukin (IL)–6 down-regulates T helper (Th) cell type 1 differentiation and drives Th2 cell differentiation. The IL6 −174 G/C polymorphism is associated with proinflammatory diseases and IL-6 regulation MethodsThe −174 G/C polymorphism was genotyped in population samples and families with CL and ML from Brazil. Genotype frequencies were compared among patients with ML, patients with CL, and 2 control groups by logistic regression and family-based association test (FBAT) analysis. IL-6 levels were measured in macrophages ResultsThe C allele was more common in patients with ML than in patients with CL (odds ratio [OR], 2.55 [95% confidence interval {CI}, 1.32–4.91]; P=.005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23–4.05]; P=.009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24–4.90]; P=.01). FBAT analysis confirmed an association between allele C and ML under both additive (z=4.295; P=.000017) and dominant (z=4.325; P=.000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (P=.003) as well as after stimulation with soluble leishmania antigen (P=.009) ConclusionsIL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.
Original languageEnglish
Pages (from-to)519-527
JournalJournal of Infectious Diseases
Volume194
Issue number4
DOIs
Publication statusPublished - 2006

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