The −2518bp promoter polymorphism at CCL2/MCP1 influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil

• Published in: Infection, genetics and evolution Vol. 10; no. 5; pp. 607 - 613
• Main Authors: Ramasawmy, Rajendranath, Menezes, Eliane, Magalhães, Andrea, Oliveira, Joyce, Castellucci, Léa, Almeida, Roque, Rosa, Maria Elisa A., Guimarães, Luiz Henrique, Lessa, Marcus, Noronha, Elza, Wilson, Mary E., Jamieson, Sarra E., Kalil, Jorge, Blackwell, Jenefer M., Carvalho, Edgar M., de Jesus, Amélia Ribeiro
• Format: Journal Article
• Language: English
• Published: Netherlands 01.07.2010
• Subjects: Adult; Animals; Brazil; Case-Control Studies; Chemokine CCL2 - genetics; Cytokines - immunology; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leishmania braziliensis; Leishmaniasis, Cutaneous - genetics; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Mucocutaneous - genetics; Leishmaniasis, Mucocutaneous - immunology; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Brazil
• ISSN: 1567-1348; 1567-7257; 1567-7257
• DOI: 10.1016/j.meegid.2010.04.006

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.