title: Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil.
abstract: Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by Leishmania major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in the TGF beta pathway. Haplotype tagging single nucleotide polymorphisms (tag-SNPs) were genotyped using Taqman technology in 325 nuclear families (652 CL cases; 126 ML cases) from Brazil. Robust case-pseudocontrol (CPC) conditional logistic regression analysis showed associations between CL and SNPs at CTGF (SNP rs6918698; CC genotype; OR 1.67; 95%CI 1.10-2.54; P=0.016), TGFBR2 (rs1962859; OR 1.50; 95%CI 1.12-1.99; P=0.005), SMAD2 (rs1792658; OR 1.57; 95%CI 1.04-2.38; P=0.03), SMAD7 (rs4464148; AA genotype; OR 2.80; 95%CI 1.00-7.87; P=0.05) and FLII (rs2071242; OR 1.60; 95%CI 1.14-2.24; P=0.005), and between ML and SNPs at SMAD3 (rs1465841; OR 2.15; 95%CI 1.13-4.07; P=0.018) and SMAD7 (rs2337107; TT genotype; OR 3.70; 95%CI 1.27-10.7; P=0.016). Stepwise logistic regression analysis showed that all SNPs associated with CL at FLI1, CTGF, TGFBR2, and FLII showed independent effects from each other, but SNPs at SMAD2 and SMAD7 did not add independent effects to SNPs from other genes. These results suggest that TGFβ signalling via SMAD2 is important in directing events that contribute to CL, whereas signalling via SMAD3 is important in ML. Both are modulated by the inhibitory SMAD7 that acts upstream of SMAD2 and SMAD3 in this signalling pathway. Along with the published FLI1 association, these data further contribute to the hypothesis that wound healing processes are important determinants of pathology associated with cutaneous forms of leishmaniasis.
authors.affiliation: National Institute of Science and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil. leacastel@hotmail.com
authors.forename: Léa
authors.initials: L
authors.lastname: Castellucci
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.forename: Lucas
authors.initials: L
authors.lastname: Almeida
authors.forename: Joyce
authors.initials: J
authors.lastname: Oliveira
authors.forename: Luiz Henrique
authors.initials: LH
authors.lastname: Guimarães
authors.forename: Marcus
authors.initials: M
authors.lastname: Lessa
authors.forename: Michaela
authors.initials: M
authors.lastname: Fakiola
authors.forename: Amélia Ribeiro de
authors.initials: AR
authors.lastname: Jesus
authors.forename: E
authors.initials: E
authors.lastname: Nancy Miller
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D001938:Brazil / Q000453:epidemiology; D015331:Cohort Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D016773:Leishmaniasis, Cutaneous / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000235:genetics; D014945:Wound Healing / Q000235:genetics*
chemical_list: C098179:FLII protein, human; D008840:Microfilament Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D016212:Transforming Growth Factor beta