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FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil

Genes & Immunity volume 12, pages 589–594 (2011)Cite this article

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Abstract

Mapping murine genes controlling cutaneous leishmaniasis (CL) identified Fli1 as a candidate influencing resistance to L. major and enhanced wound healing. We examine FLI1 as a gene controlling CL and mucosal leishmaniasis (ML) caused by L. braziliensis in humans. Intron 1 single nucleotide polymorphisms tagging promoter and enhancer elements were analysed in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Robust case-pseudocontrol logistic regression analysis showed association between allele C (odds ratio (OR) 1.65; 95% confidence interval 1.18–2.29; P=0.003) of FLI1_rs7930515 and CL in the primary sample that was confirmed (OR 1.60; 95% confidence interval 1.10–2.33; P=0.014) in the replication set (combined P=1.8 × 10−4). FLI1_rs7930515 is in linkage disequilibrium with the functional GAn microsatellite in the proximal promoter. Haplotype associations extended across the enhancer, which was not polymorphic. ML associated with inverse haplotypes compared with CL. Wound healing is therefore important in CL, providing potential for therapies modulating FLI1.

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Acknowledgements

We acknowledge the support of NIH Grant AI 30639 for the field work in Brazil, and The Wellcome Trust for supporting the laboratory work and statistical analyses carried out in the UK. LC was supported by NIH/FIC 1 D43 TW007127–01 for her period of stay in UK. JO and AM were also supported by NIH/FIC 1 D43 TW007127-01 in Brazil.

Authors contributions: LC carried out the field collection and preparation of the samples, performed the genotyping, and participated in the statistical analysis and interpretation of the data. SEJ and ENM trained LC in the laboratory for genotyping techniques, in database entry and use of the genetic database GenIE in Cambridge, and in genetic statistical analysis methods. SEJ cross-checked statistical analyses and carried out additional statistical tests. LFA, JO, AM and LHG participated in the field collection of data, processing of DNA samples and database entry in Brazil. ML is the doctor responsible for confirmation of the ML cases by performing ENT exams. EL participated in the field work by contacting patients and helping sample collection. ARJ trained the field group, initial selection of cases from the health post, assisted with field collection of data and participated in the design of the study. EMC helped conceive the study, initial selection of cases from the health post and provided the logistical support to make the study possible. JMB participated in the design of the study, conceived the specific hypothesis to be tested, made the final interpretation of the data and prepared the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Federal University of Bahia, Salvador, Brazil

    L Castellucci, L F de Almeida, J Oliveira, A Magalhães, L H Guimarães, M Lessa, E Lago, A R de Jesus & E M Carvalho

  2. Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK

    L Castellucci, S E Jamieson, E N Miller & J M Blackwell

  3. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia

    S E Jamieson & J M Blackwell

  4. Instituto de Investigação em Imunologia, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil

    A R de Jesus

  5. Departmento de Medicina, Universidade Federal de Sergipe, Aracaju, Brazil

    A R de Jesus

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  1. L Castellucci
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  2. S E Jamieson
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  3. E N Miller
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  4. L F de Almeida
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  9. E Lago
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Correspondence to J M Blackwell.

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Castellucci, L., Jamieson, S., Miller, E. et al. FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil. Genes Immun 12, 589–594 (2011). https://doi.org/10.1038/gene.2011.37

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