Abstract:
|
Genetic susceptibility to visceral leishmaniasis (VL) is indicated by differences in incidence and clinical
phenotypes between ethnic groups in Sudan. In mice, innate susceptibility to Leishmania donovani, the
etiological agent of VL, is controlled by Slc11a1 (formerly Nramp1). We therefore examined
polymorphisms at SLC11A1 in 59 multicase families of VL from the high-incidence Masalit tribe in Sudan.
Multipoint nonparametric analysis in ALLEGRO shows a significant linkage across SLC11A1 (Zlr scores 2.38–
2.55; 0.008pPp0.012; information content 0.88). The extended transmission disequilibrium test shows
biased transmission of alleles at 50 polymorphisms in the promoter (P¼0.0145), exon 3 (P¼0.0037) and
intron 4 (P¼0.0049), and haplotypes formed by them (P¼0.0089), but not for 30 polymorphisms at exon
15 or the 30UTR. Stepwise logistic regression analysis using a case/pseudo-control data set derived from
the 59 families was consistent with main effects contributed by the intron 4 469þ14G/C polymorphism.
Although the two alleles for 469þ14G/C lie on haplotypes carrying different alleles for the functional
promoter GTn polymorphism, the latter did not itself contribute separate main effects. Sequence analysis
of 36 individuals failed to identify new putative functional polymorphisms in the coding region, intron 1,
intron/exon boundaries, intron 4/exon 4a, or in the 30UTR. One novel promoter polymorphism (–86G/A)
was located within a putative nuclear factor kappa B binding site that could be functional. Further work will
determine whether additional polymorphisms occur upstream in the promoter, which could be in linkage
disequilibrium with the intron 4 polymorphism. These studies contribute to knowledge of the role of
SLC11A1 in infectious disease. |