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

Background. Mucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor-alpha and interferon-gamma 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]; 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 (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). Conclusions. IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.