Trends in Parasitology
Genetics and visceral leishmaniasis in the Sudan: seeking a link
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
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