Genetic risk factors for Visceral Leishmaniasis in Bihar, India

利什曼病(VL)发生在印度/孟加拉国/尼泊尔、苏丹和巴西。临床VL与 反复发烧，肝脾肿大，全身淋巴结病，全血细胞减少和贫血，并是致命的 除非接受治疗。然而，约80%-90%的人类感染会导致无症状或亚临床疾病。这个 这个项目的长期目标是了解决定为什么两个 同样暴露在感染环境中的人对临床疾病的易感性不同。这将提供 在确定改进的治疗干预策略方面的重要线索。 项目描述：为了确定与VL发病有关的基因/机制/途径，我们将：(1) 继续建立用于连锁研究的VL多酶系家系资源，以及用于等位基因研究的病例-亲本三元组 在整个TMPC期间，协会进行研究，最终目的是建立至少 1000个病例-父母三人组的资源，可用于重新评估先前的候选基因研究和 2q12-q14.1、6p25.3-p25.1、8p23.1、11q14.1-q22.3和Xq21.31-q25) 我们之前在印度多酶基因家系中进行的VL连锁基因组扫描 在初级和附加多酶切家系中增加微卫星标记并进行连锁 分析；(3)确定Y染色体单倍型的基因SNPs在家系中的应用 这些标记用于通过按Y对连锁分析进行分层来寻找特定于家族的易感基因座 染色体单倍型；(4)确定连锁高峰下仍为阳性的致病基因 在通过基因分型单倍型标记SNPs在多酶家族和Trio中进行精细定位后，以及 进行基于家系的等位基因关联测试；(5)对可能的致病基因进行重新测序 连锁高峰下的等位基因关联，以识别与疾病相关的功能变异；以及(6) 研究所有VL易感基因(即在印度和印度发现的基因)的表达/本地化 非印度人群)来自患者和/或外周的脾活检材料中的RNA和蛋白质水平 有或没有来自患者和接触者的特定抗原刺激的血细胞。

Lay statement: Ninety percent of the 500,000 annual new cases of Kala-azar or clinical visceral leishmaniasis (VL) occur in India/Bangladesh/Nepal, Sudan and Brazil. Clinical VL is associated with recurrent fever, hepatosplenomegaly, general lymphadenopathy, pancytopenia and anemia, and is fatal unless treated. However, ~80-90% of human infections result in asymptomatic or sub-clinical disease. The long-term objective of this project is to understand the genes and mechanisms that determine why two people with the same exposure to infection differ in susceptibility to clinical disease. This will provide important leads in determining improved strategies for therapeutic intervention. Project description: To identify genes/mechanisms/pathways that contribute to VL pathogenesis we will: (1) continue to build the resource of multicase families of VL for linkage studies, and case-parent trios for allelic association studies, throughout the course of the TMPC period, with the ultimate aim of building a minimum resource of 1000 case-parent trios that that can be used to re-evaluate previous candidate gene studies and to undertake a SNP-chip allelic association study; (2) refine map regions (minimally chromosomes 1p13.1, 2q12-q14.1, 6p25.3-p25.1, 8p23.1, 11q14.1-q22.3 and Xq21.31-q25) of the genome positive on a primary linkage genome scan for VL previously undertaken by us on Indian multicase families by genotyping additional micro-satellite markers in the primary and additional multicase families and carrying out linkage analysis; (3) genotype SNPs to determine Y chromosome haplotypes for founding males in families and use these as tags to look for lineage-specific susceptibility loci by stratifying the linkage analysis by Y chromosome haplotype; (4) identify the etiological genes under the peaks of linkage that remain positive after refined mapping by genotyping haplotype tagging SNPs in both multicase families and trios, and carrying out family based allelic association tests; (5) re-sequence the putative etiological genes that show allelic association under the linkage peaks to identify the functional variants associated with disease; and (6) study expression/localization of the products of all VL susceptibility genes (i.e. those identified in Indian and non-Indian populations) at RNA and protein levels in splenic biopsy material from patients, and/or peripheral blood cells with/without specific antigenic stimulation from patients and contacts.