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: 8134247
• 负责人: SHYAM SUNDAR
• 金额: $ 23.24万
• 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/8134247
• 关键词: 1p13.1; 2q12; 6p25.3; 8p23.1; Anemia; Bangladesh; Biopsy; Blood Cells; Brazil; Candidate Disease Gene; Case Study; Chromosomes; Clinical; Disease; Exposure to; Family; Fever; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genome Scan; Genotype; Geographic Locations; Haplotypes; Hepatosplenomegaly; Human; India; Infection; Knowledge; 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 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.

非正式声明：每年50万例黑热病或临床内脏感染新病例中有90% 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、全身淋巴结病、全血细胞减少和贫血，并且是致命的 除非治疗。然而，约80-90%的人类感染导致无症状或亚临床疾病。的 该项目的长期目标是了解基因和机制，决定为什么两个 同样暴露于感染的人对临床疾病的易感性不同。这将提供 在确定治疗干预的改进策略中的重要线索。 项目描述：为了确定导致VL发病的基因/机制/途径，我们将：（1） 继续建立VL的多酶系资源用于连锁研究，建立VL的病例-亲本三联体资源用于等位基因的连锁研究， 协会研究，在整个TMPC期间，最终目的是建立一个最低限度的 1000个病例-亲本三联体的资源，可用于重新评估先前的候选基因研究， 进行SNP-芯片等位基因关联研究;（2）细化图谱区域（最小染色体1p13.1， 2 q12-q14.1、6p25.3-p25.1、8p23.1、11q14.1-q22.3和Xq21.31-q25）的基因组在原发性 我们先前通过基因分型对印度多酶家族进行的VL连锁基因组扫描 在一级和附加多核家系中附加微卫星标记， 分析;（3）基因型SNP，以确定Y染色体单倍型，用于家族中的创始男性和使用 这些作为标签，通过Y染色体的连锁分析来寻找谱系特异性易感基因座。 染色体单倍型;（4）确定连锁峰下仍保持阳性的致病基因 在通过对多酶家族和三酶家族中的单倍型标记SNP进行基因分型进行精细作图后， 进行基于家族的等位基因关联测试;（5）重新测序推定的致病基因， 连锁峰下的等位基因关联，以鉴定与疾病相关的功能变体;和（6） 研究所有VL易感基因产物的表达/定位（即在印度和 非印度人群），和/或外周血淋巴细胞 有/没有来自患者和接触者的特异性抗原刺激的血细胞。