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 (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).


CONCLUSIONS
IL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.
Castellucci
Lea
L
Servico de Imunologia, Hospital Universitario Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brazil.
Menezes
Eliane
E
Oliveira
Joyce
J
Magalhaes
Andrea
A
Guimaraes
Luiz Henrique
LH
Lessa
Marcus
M
Ribeiro
Silvana
S
Reale
Jeancarlo
J
Noronha
Elza Ferreira
EF
Wilson
Mary E
ME
Duggal
Priya
P
Beaty
Terri H
TH
Jeronimo
Selma
S
Jamieson
Sarra E
SE
Bales
Ashlee
A
Blackwell
Jenefer M
JM
de Jesus
Amelia Ribeiro
AR
Carvalho
Edgar M
EM
D000328:Adult; D000818:Animals; D001938:Brazil / Q000453:epidemiology; D016022:Case-Control Studies; D005260:Female; D006798:Housing; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D007892:Leishmania braziliensis; D016773:Leishmaniasis, Cutaneous / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors
D015850:Interleukin-6