IL6 −174 G/C Promoter Polymorphism Influences Susceptibility to Mucosal but Not Localized Cutaneous Leishmaniasis in Brazil

Abstract

Background. Mucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor–a and interferon- g 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. Methods. The 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. Results. The 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]; Pp.005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23–4.05]; Pp.009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24–4.90]; Pp.01). FBAT analysis confirmed an association between allele C and ML under both additive (zp4.295; Pp.000017) and dominant (zp4.325; Pp.000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (Pp.003) as well as after stimulation with soluble leishmania antigen (Pp.009). Conclusions. IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.