title: SLC11A1 (formerly NRAMP1) and susceptibility to visceral leishmaniasis in The Sudan.
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; 0.008< or =P< or =0.012; information content 0.88). The extended transmission disequilibrium test shows biased transmission of alleles at 5' polymorphisms in the promoter (P=0.0145), exon 3 (P=0.0037) and intron 4 (P=0.0049), and haplotypes formed by them (P=0.0089), but not for 3' polymorphisms at exon 15 or the 3'UTR. 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 4 469+14G/C polymorphism. Although the two alleles for 469+14G/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 3'UTR. 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.
authors.affiliation: Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
authors.forename: Hiba Salah
authors.initials: HS
authors.lastname: Mohamed
authors.forename: Muntaser Eltayeb
authors.initials: ME
authors.lastname: Ibrahim
authors.forename: Elinor Nancy
authors.initials: EN
authors.lastname: Miller
authors.forename: Jacqueline Katie
authors.initials: JK
authors.lastname: White
authors.forename: Heather Jane
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Joanna McCammond McGill
authors.initials: JM
authors.lastname: Howson
authors.forename: Christopher Sean
authors.initials: CS
authors.lastname: Peacock
authors.forename: Eltahir Awad Gasim
authors.initials: EA
authors.lastname: Khalil
authors.forename: Ahmed Mohamed
authors.initials: AM
authors.lastname: El Hassan
authors.forename: Jenefer Mary
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000704:Analysis of Variance; D027682:Cation Transport Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013397:Sudan; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D005819:Genetic Markers; D000099173:Natural Resistance-associated Macrophage Protein 1