Institute of Medical Sciences, Banaras Hindu University, Varanasi, OS 221 005, India.
Infect Genet Evol. 2012 Aug;12(6):1195-201. doi: 10.1016/j.meegid.2012.04.017. Epub 2012 Apr 24.
Chromosome 6q26-27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at PHF10/C6orf70/DLL1/FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and FAM120B, with top associations (rs9460106, OR=1.17, 95%CI 1.01-1.35, P=0.033; rs2103816, OR=1.16, 95%CI 1.01-1.34, P=0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; P=0.028) at FAM120B, while the most significant protective haplotype (frequency 0.18; P=0.007) was a 5-SNP haplotype across the interval 5' of both DLL1 (negative strand) and FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre- and post-treatment splenic aspirates from VL patients (N=19). DLL1 was the only gene to show differential expression that was higher (P<0.0001) in pre- compared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species.
6 号染色体 q26-27 与巴西和苏丹内脏利什曼病（VL）易感性相关。Delta-like 1 配体 DLL1 编码 Notch3 的基因被认为是病因基因。DLL1 属于 Notch 配体家族，已知其选择性地驱动抗原特异性 CD4 T 辅助 1 细胞反应，这在利什曼病的保护性免疫反应中很重要。在这里，我们提供了进一步的遗传和功能证据，支持 DLL1 在一项以印度最大的全球 VL 焦点为中心的、有影响力的基于人群的研究中的作用。在 941 例病例和 992 例对照中，对 PHF10/C6orf70/DLL1/FAM120B/PSMB1/TBP 中的 21 个单核苷酸多态性（SNP）进行了基因分型。在加性模型下进行的逻辑回归分析显示，VL 与 DLL1 和 FAM120B 变体之间存在关联，最强的关联（rs9460106，OR=1.17，95%CI 1.01-1.35，P=0.033；rs2103816，OR=1.16，95%CI 1.01-1.34，P=0.039）在使用种姓作为协变量以考虑人口亚结构的分析中是稳健的。考虑到人口亚结构的单倍型分析确定了 FAM120B 上常见的 2-SNP 风险单倍型（频率 0.43；P=0.028），而最显著的保护性单倍型（频率 0.18；P=0.007）是 DLL1 5'端（负链）和 FAM120B（正链）之间跨越 5 个 SNP 的单倍型，并延伸至 DLL1 的内含子 4。定量 RT/PCR 用于比较来自 VL 患者（N=19）的配对治疗前后脾抽吸物中 6q27 基因的表达。在治疗前和治疗后样本中，只有 DLL1 显示出差异表达，治疗前的表达更高（P<0.0001），这表明基因表达的调控在疾病发病机制中很重要。这项在印度人群中进行的有影响力的遗传和功能研究提供了证据，支持 DLL1 作为 6q27 染色体上导致 VL 易感性的病因基因，证实了 DLL1 多态性作为地理和寄生虫物种流行病学差异的遗传风险因素的潜力。
