title: The -2518bp promoter polymorphism at CCL2/MCP1 influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil.
abstract: Mucosal leishmaniasis (ML) follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Proinflammatory responses mediate CL self-healing but are exaggerated in ML. Proinflammatory monocyte chemoattractant protein 1 (MCP-1; encoded by CCL2) is associated with CL. We explore its role in CL/ML through analysis of the regulatory CCL2 -2518bp promoter polymorphism in CL/ML population samples and families from Brazil. Genotype frequencies were compared among ML/CL cases and control groups using logistic regression and the family-based association test (FBAT). MCP-1 was measured in plasma and macrophages. The GG recessive genotype at CCL2 -2518bp was more common in patients with ML (N=67) than in neighborhood control (NC; N=60) subjects (OR 1.78; 95% CI 1.01-3.14; P=0.045), than in NC combined with leishmanin skin-test positive (N=60) controls (OR 4.40; 95% CI 1.42-13.65; P=0.010), and than in controls combined with CL (N=60) patients (OR 2.78; 95% CI 1.13-6.85; P=0.045). No associations were observed for CL compared to any groups. FBAT (91 ML and 223 CL cases in families) confirmed recessive association of ML with allele G (Z=2.679; P=0.007). Higher levels of MCP-1 occurred in plasma (P=0.03) and macrophages (P<0.0001) from GG compared to AA individuals. These results suggest that high MCP-1 increases risk of ML.
authors.affiliation: Universidade Federal da Bahia, Salvador, Brazil.
authors.forename: Rajendranath
authors.initials: R
authors.lastname: Ramasawmy
authors.forename: Eliane
authors.initials: E
authors.lastname: Menezes
authors.forename: Andrea
authors.initials: A
authors.lastname: Magalhães
authors.forename: Joyce
authors.initials: J
authors.lastname: Oliveira
authors.forename: Léa
authors.initials: L
authors.lastname: Castellucci
authors.forename: Roque
authors.initials: R
authors.lastname: Almeida
authors.forename: Maria Elisa A
authors.initials: ME
authors.lastname: Rosa
authors.forename: Luiz Henrique
authors.initials: LH
authors.lastname: Guimarães
authors.forename: Marcus
authors.initials: M
authors.lastname: Lessa
authors.forename: Elza
authors.initials: E
authors.lastname: Noronha
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.forename: Amélia Ribeiro
authors.initials: AR
authors.lastname: de Jesus
mesh_terms: D000328:Adult; D000818:Animals; D001938:Brazil; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics*; D016207:Cytokines / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007892:Leishmania braziliensis; D016773:Leishmaniasis, Cutaneous / Q000235:genetics* / Q000276:immunology; D007897:Leishmaniasis, Mucocutaneous / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines