Abstract
BackgroundGenome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.Methods and FindingsWe undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.ConclusionsGWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.
Highlights
Visceral leishmaniasis (VL) is a parasitic disease primarily caused by the Leishmania donovani species complex (L. d. donovani, L. d. infantum/chagasi, and L. d. archibaldi)
Ninety percent of theestimated 500,000 annual new cases occur in India/Bangladesh/ Nepal, Brazil, and Sudan (WHO statistics on leishmaniasis http:// www.who.int/topics/leishmaniasis/en/)
India is considered an endemic site for post kala-azar dermal leishmaniasis, very few cases of this form of disease were reported in this study area [22]
Summary
Visceral leishmaniasis (VL) is a parasitic disease primarily caused by the Leishmania donovani species complex (L. d. donovani, L. d. infantum/chagasi, and L. d. archibaldi). Visceral leishmaniasis (VL) is a parasitic disease primarily caused by the Leishmania donovani species complex The remaining 80–90% of human infections is subclinical or asymptomatic, usually associated with strong cellmediated immunity to Leishmania antigen [1,2,3,4]. Genetic studies in endemic populations from Brazil and Sudan provide evidence for a number of candidate genes [11,12,13] and chromosomal regions [14,15,16,17] controlling susceptibility and resistance to VL. Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported
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