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

• Published in: The Journal of infectious diseases Vol. 204; no. 3; pp. 467 - 477
• Main Authors: Fakiola, Michaela, Miller, E. Nancy, Fadl, Manal, Mohamed, Hiba S., Jamieson, Sarra E., Francis, Richard W., Cordell, Heather J., Peacock, Christopher S., Raju, Madhuri, Khalil, Eltahir A., Elhassan, Ahmed, Musa, Ahmed M., Silveira, Fernando, Shaw, Jeffrey J., Sundar, Shyam, Jeronimo, Selma M. B., Ibrahim, Muntaser E., Blackwell, Jenefer M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2011
• Subjects: Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 6; Fundamental and applied biological sciences. Psychology; Genes; Genetic Predisposition to Disease; Genomics; Genotype; Haplotypes; Human protozoal diseases; Humans; Infectious diseases; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - physiology; Leishmaniasis, Visceral - genetics; Leshmaniasis; Ligands; Major and Brief Reports; Medical genetics; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - physiology; Microbiology; PARASITES; Parasitic diseases; Polymorphism, Single Nucleotide; Protozoal diseases; Spleen; T lymphocytes; Trios; Visceral leishmaniasis; Infection; Protozoal disease; Chromosome; Genetics; Kala azar; Leishmaniasis; Parasitosis
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jir284

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, DLLI, 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 = 3 x 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 x 10⁷) 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 x 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.