Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
20/10/2012
20/10/2012
2011
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Resumo |
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 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 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 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. Wellcome Trust Wellcome Trust[074196/Z/04/Z] |
Identificador |
JOURNAL OF INFECTIOUS DISEASES, v.204, n.3, p.467-477, 2011 1537-6613 http://producao.usp.br/handle/BDPI/28502 10.1093/infdis/jir284 |
Idioma(s) |
eng |
Publicador |
OXFORD UNIV PRESS INC |
Relação |
Journal of Infectious Diseases |
Direitos |
restrictedAccess Copyright OXFORD UNIV PRESS INC |
Palavras-Chave | #REGULATORY ELEMENTS #EASTERN SUDAN #NOTCH LIGANDS #TGF-BETA #TRANSMISSION/DISEQUILIBRIUM TEST #CASE/PSEUDOCONTROL ANALYSIS #NONCODING SEQUENCES #NORTHEASTERN BRAZIL #DONOVANI INFECTION #MULTIPLE ALIGNMENT #Immunology #Infectious Diseases #Microbiology |
Tipo |
article original article publishedVersion |