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Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27

Year: 2011

Type: article

Abstract: Background.Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum chagasi.Genome-wide linkage studies from Sudan and Brazil identified a putative susceptibility locus on chromosome 6q27. Methods.Twenty-two single-nucleotide polymorphisms (SNPs) at genes PHF10, C6orf70, DLL1, FAM120B, PSMB1, and TBP were genotyped in 193 VL cases from 85 Sudanese families, and 8 SNPs at genes PHF10, C6orf70, DLL1, PSMB1, and TBP were genotyped in 194 VL cases from 80 Brazilian families.Family-based association, haplotype, and linkage disequilibrium analyses were performed.Multispecies comparative sequence analysis was used to identify conserved noncoding sequences carrying putative regulatory elements.Quantitative reversetranscription polymerase chain reaction measured expression of candidate genes in splenic aspirates from Indian patients with VL compared with that in the control spleen sample.Results.Positive associations were observed at PHF10, C6orf70, DLL1, PSMB1, and TBP in Sudan, but only at DLL1 in Brazil (combined P 5 3 3 10 24 at DLL1 across Sudan and Brazil).No functional coding region variants were observed in resequencing of 22 Sudanese VL cases.DLL1 expression was significantly (P 5 2 3 10 27 ) reduced (mean fold change, 3.5 [SEM, 0.7]) in splenic aspirates from patients with VL, whereas other 6q27 genes showed higher levels (1.27 3 10 26 , P , .01)than did the control spleen sample.A cluster of conserved noncoding sequences with putative regulatory variants was identified in the distal promoter of DLL1.Conclusions.DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene.Ninety percent of visceral leishmaniasis (VL) cases caused by the Leishmania donovani complex occur in India/Bangladesh/Nepal, Brazil, and Sudan.The disease is characterized by parasitization of the spleen, liver, lymph nodes, and bone marrow and is fatal if left untreated in the 10%-20% of infected individuals who are susceptible.VL is listed as a neglected disease by the World Health Organization.Large-scale epidemics with high mortality rates have occurred in rural areas of Sudan and India.Outbreaks in Brazil are often peri-urban.Host genetic factors are indicated by familial clustering [1, 2], ethnic differences [3], and high sibling risk ratios [4].Family-based genome-wide linkage studies (GWLSs) (reviewed by Blackwell et al [5]) identified chromosome 6q26-q27 as a region of interest in eastern Sudan [6], with a major village-specific peak of linkage

Source: The Journal of Infectious Diseases

DOI: 10.1093/infdis/jir284