Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, UK.
J Infect Dis. 2011 Aug 1;204(3):467-77. doi: 10.1093/infdis/jir284.
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.
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.
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.
DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene.
内脏利什曼病（VL）是由利什曼原虫和恰加斯利什曼原虫引起的。来自苏丹和巴西的全基因组连锁研究在 6q27 染色体上确定了一个假定的易感基因座。
在来自 85 个苏丹家庭的 193 例 VL 病例和来自 80 个巴西家庭的 194 例 VL 病例中，对 PHF10、C6orf70、DLL1、FAM120B、PSMB1 和 TBP 基因的 22 个单核苷酸多态性（SNP）进行了基因分型。对基因 PHF10、C6orf70、DLL1、PSMB1 和 TBP 的 8 个 SNP 进行了基因分型。进行了基于家族的关联、单倍型和连锁不平衡分析。使用多物种比较序列分析来鉴定携带假定调控元件的保守非编码序列。采用定量逆转录聚合酶链反应测量来自印度 VL 患者的脾抽吸物中候选基因的表达，与对照脾样本进行比较。
在苏丹观察到 PHF10、C6orf70、DLL1、PSMB1 和 TBP 的阳性关联，但在巴西仅观察到 DLL1 的阳性关联（苏丹和巴西合并 P = 3×10(-4) ）。在对 22 例苏丹 VL 病例的重测序中未观察到功能编码区变异。DLL1 表达在 VL 患者的脾抽吸物中显著降低（P = 2×10(-7)）（平均 fold change，3.5[SEM，0.7]），而其他 6q27 基因的表达水平高于对照脾样本（P<0.01）。在 DLL1 的远端启动子中发现了一个具有假定调控变异的保守非编码序列簇。
编码 Notch3 配体 Delta-like 1 的 DLL1 强烈暗示为 6q27 VL 易感基因。
