Trends in Parasitology
Volume 20, Issue 6, 1 June 2004, Pages 268-274
Journal home page for Trends in Parasitology

Genetics and visceral leishmaniasis in the Sudan: seeking a link

https://doi.org/10.1016/j.pt.2004.04.003Get rights and content

Abstract

With the human genome sequence in hand, emphasis is now focusing on genetic diversity and its role in susceptibility to disease. In the Sudan, different tribes share the same exposure to Leishmania donovani, but only certain tribes are at risk of clinical disease. This suggests that host genotype is important, with genes controlling innate and adaptive immunity likely to be involved. Using multicase families, linkage and allelic association has been demonstrated between clinical visceral leishmaniasis (VL) and the innate resistance gene SLC11A1 (formerly NRAMP1), which regulates macrophage activation. Polymorphism at IL4 is also associated with underlying susceptibility to VL, whereas IFNGR1 is associated specifically with post-kala-azar dermal leishmaniasis.

Section snippets

Creating a resource for genetic studies

An appropriate resource of DNA is needed to study genetic susceptibility. We elected to focus initially on identifying genetic variants among the Masalit tribe that might contribute to their susceptibility to clinical disease. Because multiple cases in the same families had frequently been observed, a resource of families is appropriate to look for linkage between polymorphic variants in candidate genes and susceptibility to VL (Box 1). When looking for linkage, highly polymorphic, and

Role of innate resistance gene SLC11A1

Recent interest in immunology has focused on the role of innate immunity in driving the adaptive immune response, particularly in relation to intra-macrophage pathogens. In mice, the archetypal innate resistance gene was first identified as a gene controlling VL caused by L. donovani sensu strictu (reviewed in Ref. [8]). This gene, originally designated Lsh, Ity or Bcg, was also shown to influence innate resistance to Salmonella typhimurium, Mycobacterium bovis BCG, Mycobacterium lepraemurium

Genes associated with Th1 versus Th2 responses

Clinical VL in the Sudan is a complex disease phenotype so we expect multiple genes to influence susceptibility to disease. In particular, genes that regulate induction of an adaptive T-cell response will be important. For example, in the mouse [27], the correct haplotype at the major histocompatibility complex (MHC; HLA in humans, H-2 in mice) controlling adaptive immunity can overcome innate susceptibility caused by mutation at Slc11a1. Extensive analysis of polymorphisms across the class II

Conclusions

Recent genetic studies of VL 5, 7, 30 and PKDL 5, 30 have begun to identify the genes and polymorphisms that are involved in determining susceptibility to L. donovani infection in the Sudan. Because the clinical disease pattern is complex, it is likely that other genes that regulate innate and adaptive immunity could be involved. As outlined in Figure 2, many good candidates have yet to be analysed. As with studies of susceptibility to mycobacterial infections, the first important demonstration

Acknowledgements

We thank the people of the Sudan who have contributed to our studies. We also thank E. Khalil and the field and laboratory teams in the Sudan for their enormous effort and support, and A. Elhassan for his mentorship, encouragement and enthusiasm for our work. We thank E.N. Miller and H. Cordell for guiding us through the genetic statistical analyses, J. White for masterminding the sequencing initiative, and B. Gilmartin for assistance with bioinformatics and preparation of Figure 1. The work

Glossary

Glossary

Allelic association:
statistical comparison of marker allele frequencies between a disease group and a control group, used to suggest genes and regions that might influence disease risk.
Candidate gene:
a gene selected for study because it is either (i) known to be located by linkage analysis in a region of interest, or (ii) previous or existing data have implicated the gene or its variants in a plausible disease model.
Case/control analysis:
a study design based upon the comparison of cases and

References (57)

  • E.E. Zijlstra et al.

    Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis

    Trans. R. Soc. Trop. Med. Hyg.

    (2001)
  • A. Kong et al.

    Allele-sharing models: LOD scores and accurate linkage tests

    Am. J. Hum. Genet.

    (1997)
  • F. Dudbridge

    Unbiased application of the transmission disequilibrium test to multilocus haplotypes

    Am. J. Hum. Genet.

    (2000)
  • P. De Beer

    Outbreak of kala-azar in the Sudan

    Lancet

    (1990)
  • E.E. Zijlstra

    Endemic kala-azar in Eastern Sudan, a longitudinal study on the incidence of clinical and subclinical infection and post-kala-azar dermal leishmaniasis

    Am. J. Trop. Med. Hyg.

    (1994)
  • M.E. Ibrahim

    Kala-azar in a high transmission focus: an ethnic and geographical dimension

    Am. J. Trop. Med. Hyg.

    (1999)
  • H.S. Mohamed

    Genetic susceptibility to visceral leishmaniasis in the Sudan: linkage and association with IL4 and IFNGR1

    Genes Immun.

    (2003)
  • H.S. Mohamed

    SLC11A1 (formerly NRAMP1) and susceptibility to visceral leishmaniasis in the Sudan

    Eur. J. Hum. Genet.

    (2004)
  • B. Bucheton

    Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region

    Genes Immun.

    (2003)
  • J.M. Blackwell

    SLC11A1 (formerly NRAMP1) and disease

    Cell. Microbiol.

    (2001)
  • T. Goswami

    Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter

    Biochem. J.

    (2001)
  • S. Vidal

    The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene

    J. Exp. Med.

    (1995)
  • S. Searle

    Localization of Nramp1 in macrophages: modulation with activation and infection

    J. Cell Sci.

    (1998)
  • R. Bellamy

    Variation in the NRAMP1 gene is associated with susceptibility to tuberculosis in West Africans

    N. Engl. J. Med.

    (1998)
  • S. Marquet

    Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility

    J. Infect. Dis.

    (1999)
  • S. Searle et al.

    Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility

    J. Med. Genet.

    (1999)
  • J.M. Blackwell

    Genomic organization and sequence of the human NRAMP gene: identification and mapping of a promoter region polymorphism

    Mol. Med.

    (1995)
  • J. Liu

    Identification of polymorphisms and sequence variants in human homologue of the mouse natural resistance-associated macrophage protein gene

    Am. J. Hum. Genet.

    (1995)
  • Cited by (0)

    View full text