title: CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study.
abstract: BACKGROUND
  L. braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. Wound healing neutrophil (PMN) and macrophage responses made following the bite of the vector sand fly contribute to disease progression in mice. To look at the interplay between PMN and macrophages in disease progression in humans we asked whether polymorphisms at genes that regulate their infiltration or function are associated with different clinical phenotypes. Specifically, CXCR1 (IL8RA) and CXCR2 (IL8RB) are receptors for chemokines that attract PMN to inflammatory sites. They lie 30-260 kb upstream of SLC11A1, a gene known primarily for its role in regulating macrophage activation, resistance to leishmaniasis, and wound healing responses in mice, but also known to be expressed in PMN, macrophages and dendritic cells.
  
  
  METHODS
  Polymorphic variants at CXCR1, CXCR2 and SLC11A1 were analysed using Taqman or ABI fragment separation technologies in cases (60 CL; 60 ML), unrelated controls (n = 120), and multicase families (104 nuclear families; 88 ML, 250 CL cases) from Brazil. Logistic regression analysis, family-based association testing (FBAT) and haplotype analysis (TRANSMIT) were performed.
  
  
  RESULTS
  Case-control analysis showed association between the common C allele (OR 2.38; 95% CI 1.23-4.57; P = 0.009) of CXCR1_rs2854386 and CL, supported by family-based (FBAT; Z score 2.002; P = 0.045) analysis (104 nuclear families; 88 ML, 250 CL cases). ML associated with the rarer G allele (Z score 1.999; P = 0.046). CL associated with a 3' insertion/deletion polymorphism at SLC11A1 (Z score 2.549; P = 0.011).
  
  
  CONCLUSIONS
  The study supports roles for CXCR1 and SLC11A1 in the outcome of L. braziliensis infection in humans. Slc11a1 does not influence cutaneous lesion development following needle injection of Leishmania in mice, suggesting that its role here might relate to the action of PMN, macrophage and/or dendritic cells in the wound healing response to the sand fly bite. Together with the CXCR1 association, the data are consistent with hypotheses relating to the possible role of PMN in initiation of a lesion following the delivery of parasites via the sand fly bite. Association of ML with the rare derived G allele suggests that PMN also have an important positive role to play in preventing this form of the disease.
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Léa
authors.initials: L
authors.lastname: Castellucci
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.forename: E Nancy
authors.initials: EN
authors.lastname: Miller
authors.forename: Eliane
authors.initials: E
authors.lastname: Menezes
authors.forename: Joyce
authors.initials: J
authors.lastname: Oliveira
authors.forename: Andrea
authors.initials: A
authors.lastname: Magalhães
authors.forename: Luiz Henrique
authors.initials: LH
authors.lastname: Guimarães
authors.forename: Marcus
authors.initials: M
authors.lastname: Lessa
authors.forename: Amélia Ribeiro
authors.initials: AR
authors.lastname: de Jesus
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001938:Brazil; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D016773:Leishmaniasis, Cutaneous / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D016015:Logistic Models; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009504:Neutrophils / Q000276:immunology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D023062:Receptors, Interleukin-8A / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000235:genetics; D055815:Young Adult; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D000099173:Natural Resistance-associated Macrophage Protein 1