title: Genetic and functional evidence implicating DLL1 as the gene that influences susceptibility to visceral leishmaniasis at chromosome 6q27.
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 reverse-transcription 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 = 3 × 10(-4) 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 = 2 × 10(-7)) 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 × 10(-6) < 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.
authors: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, UK.
authors: Michaela
authors: M
authors: Fakiola
authors: E Nancy
authors: EN
authors: Miller
authors: Manal
authors: M
authors: Fadl
authors: Hiba S
authors: HS
authors: Mohamed
authors: Sarra E
authors: SE
authors: Jamieson
authors: Richard W
authors: RW
authors: Francis
authors: Heather J
authors: HJ
authors: Cordell
authors: Christopher S
authors: CS
authors: Peacock
authors: Madhuri
authors: M
authors: Raju
authors: Eltahir A
authors: EA
authors: Khalil
authors: Ahmed
authors: A
authors: Elhassan
authors: Ahmed M
authors: AM
authors: Musa
authors: Fernando
authors: F
authors: Silveira
authors: Jeffrey J
authors: JJ
authors: Shaw
authors: Shyam
authors: S
authors: Sundar
authors: Selma M B
authors: SM
authors: Jeronimo
authors: Muntaser E
authors: ME
authors: Ibrahim
authors: Jenefer M
authors: JM
authors: Blackwell
mesh_terms: D002135:Calcium-Binding Proteins; D002896:Chromosomes, Human, Pair 6; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins