Genetics and visceral leishmaniasis: of mice and man

Abstract

Ninety per cent of the 500,000 annual new cases of visceral leishmaniasis (VL) occur in India/Bangladesh/Nepal, Sudan and Brazil. Importantly, 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity. Understanding the environmental and genetic risk factors that determine why two people with the same exposure to infection differ in susceptibility could provide important leads for improved therapies. Recent research using candidate gene association analysis and genome-wide linkage studies (GWLS) in collections of families from Sudan, Brazil and India have identified a number of genes/regions related both to environmental risk factors (e.g. iron), as well as genes that determine type 1 vs. type 2 cellular immune responses. However, until now all of the allelic association studies carried out have been underpowered to find genes of small effect sizes (odds ratios or OR < 2), and GWLS using multicase pedigrees have only been powered to find single major genes, or at best oligogenic control. The accumulation of large DNA banks from India and Brazil now makes it possible to undertake genome-wide association studies (GWAS), which are ongoing as part of phase 2 of the Wellcome Trust Case Control Consortium. Data from this analysis should seed research into novel genes and mechanisms that influence susceptibility to VL.

Figure 1

Percent power (Y-axis) of N=500 (A) or N=1000 (B,C) trios of case-control pairs to detect allelic association for a risk allele with effect size (OR) 1.5 (A,C) or 2 (B), given different risk allele frequencies (X-axis) and P-values (10^-2 to 10^-7 as indicated on key for different lines on each graph). Greater robustness to type one error, i.e. lower thresholds for P-values, is required for GWAS (cf. in text).

Figure 2

Diagrammatic representation of the 5q23-q31 region showing results of allelic association studies for VL, DTH+ and DTH- phenotypes in Natal, Brazil. Dotted black arrows with grey filling indicate markers with significant DTH+ associations; dotted black arrows with white filling indicate markers with significant DTH- associations. Markers D and O show independent main effects, indicating that two genes influence DTH-. For DTH+, markers L, M and N are in strong LD and do not show independent effects from each other, but do show independent effects compared to the markers R, T and U. Similarly, markers R, T and U are in LD with each other but not with L, M and N and show independent effects from L, M and N. Within this cluster, R and U show independent effects from each other. Figure adapted from [32].