Genetic risk factors for Visceral Leishmaniasis in Bihar, India

印度比哈尔邦内脏利什曼病的遗传风险因素

• 批准号: 7673883
• 负责人: SHYAM SUNDAR
• 金额: $ 26.56万
• 依托单位: BANARAS HINDU UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7673883
• 关键词: 1p13.1; 2q12; 6p25.3; 8p23.1; Anemia; Bangladesh; Biopsy; Blood Cells; Brazil; Candidate Disease Gene; Case Study; Chromosomes; Clinical; Disease; Enlargement of lymph nodes; Exposure to; Family; Fever; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genome Scan; Genotype; Geographic Locations; Haplotypes; Hepatosplenomegaly; Human; India; Infection; Knowledge; Leishmaniasis; Lymphatic Diseases; Maps; Microsatellite Repeats; Nepal; Pancytopenia; Parents; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Population; Predisposition; Proteins; RNA; Recurrence; Resources; Risk Factors; SNP genotyping; Single Nucleotide Polymorphism; Sudan; Susceptibility Gene; Testing; Therapeutic Intervention; Variant; Visceral; Visceral Leishmaniasis; Y Chromosome; base; genetic linkage analysis; genetic risk factor; improved; male

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.

外行声明：每年 50 万新发黑热病病例中的 90% 或临床内脏疾病 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 反复发热、肝脾肿大、全身淋巴结肿大、全血细胞减少和贫血，致命 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 该项目的长期目标是了解决定为什么两个 接触相同感染的人对临床疾病的易感性不同。这将提供 确定改进治疗干预策略的重要线索。 项目描述：为了确定有助于 VL 发病机制的基因/机制/途径，我们将：(1) 继续建立用于连锁研究的 VL 多病例家族资源，以及用于等位基因的病例亲本三重奏资源 在整个 TMPC 期间进行关联研究，最终目标是建立最低限度的 1000 个案例亲本三人组的资源，可用于重新评估以前的候选基因研究和 进行 SNP 芯片等位基因关联研究； (2) 细化图谱区域（至少染色体 1p13.1， 2q12-q14.1、6p25.3-p25.1、8p23.1、11q14.1-q22.3 和 Xq21.31-q25) 的基因组在原代上呈阳性 我们之前通过基因分型对印度多病例家族进行了 VL 连锁基因组扫描 主要和其他多病例家族中的附加微卫星标记并进行关联 分析; (3) 基因型 SNP 以确定 Y 染色体单倍型，用于建立家庭中的男性并使用 这些作为标签，通过 Y 分层连锁分析来寻找谱系特异性易感性位点 染色体单倍型； (4) 鉴定连锁峰下仍为阳性的致病基因 通过对多病例家族和三人组中的单倍型标记 SNP 进行基因分型进行精细定位后，以及 进行基于家族的等位基因关联测试； (5) 对显示的推定病因基因进行重新测序 连锁峰下的等位基因关联，以识别与疾病相关的功能变异；和（6） 研究所有 VL 易感基因产物的表达/定位（即在印度和印度发现的基因） 非印度人群）患者脾活检材料中的 RNA 和蛋白质水平，和/或外周血 有/没有来自患者和接触者的特定抗原刺激的血细胞。