Genetic Modulation of HbF in Beta Thalassemia

β 地中海贫血中 HbF 的基因调节

• 批准号: 7491070
• 负责人: DAVID H K CHUI
• 金额: $ 56.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491070
• 关键词: Adult; Biological; Candidate Disease Gene; Cell Differentiation process; Cells; Child; Childhood; Chinese People; Clinical; Code; Data; Epidemiologist; Erythrocytes; Erythroid Cells; Family; Frequencies; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Genotype; Globin; Goals; Guidelines; Haplotypes; Hematologist; Heterogeneity; Heterozygote; Homozygote; Hong Kong; Investigation; Laboratory Finding; Link; Linkage Disequilibrium; Maps; Molecular; Mutation; Newly Diagnosed; Parents; Patients; Phenotype; Population; Production; Quantitative Trait Loci; Regulation; Regulatory Element; Sample Size; Severity of illness; Siblings; Single Nucleotide Polymorphism; Structure; Thalassemia; Trans-Activators; Triad Acrylic Resin; Variant; alpha-Thalassemia; beta Globin; beta Thalassemia; cis acting element; density; disease phenotype; experience; gamma Globin; genetic association; genetic variant; man; novel therapeutics; patient registry; pediatrician; prognostic; size; therapeutic target; trait; transcription factor; transmission process

DESCRIPTION (provided by applicant): Thalassemias are man's most common Mendelian trait. Severe beta-thalassemia results from compound heterozygosity or homozygosity for mutations that abolish or impair beta-globin gene expression. The disease severity varies considerably, even among those with identical beta-thalassemia mutations and when known epistatic genetic factors, such as alpha-thalassemia, are considered. Most of this heterogeneity can be linked to the capacity to produce HbF. We hypothesize that there is genetic variation in cis-acting elements and trans-acting factors implicated in gamma-globin gene expression, in modulation of HbF concentration within erythrocytes, and in regulation of erythroid cell differentiation and proliferation. We wish to identify these genetic variations. Our 1st aim is to identify informative single nucleotide polymorphisms (SNPs) and haplotype structures in about 150 candidate genetic loci, by studying 30 family triads, each with 2 parents and 1 child. Using the haplotype tagging SNPs discovered in aim 1, our 2nd aim is to discover genetic loci and genes associated with F-cell/HbF levels, by studying about 1,000 beta-thalassemia carriers. SNP and haplotype data will be used in an F-cell/HbF quantitative trait locus (QTL) analysis. The 3rd aim is to correlate the genetic loci and genes found to be associated with F-cell/HbF levels to disease phenotypes, by studying about 320 severe beta-thalassemia patients. Our long-term goal is to identify genes of importance in HbF expression, and to investigate their biological and pathophysiological functions. A patient registry of sufficient size to accomplish these aims has been established in Hong Kong. We have formed an interactive and cohesive team of pediatricians, hematologists, geneticists, molecular biologists, epidemiologists, bioinformaticians, and statisticians who together are experienced in the proposed clinical/genetic approaches. The results of this investigation will prepare us to understand the function of potentially important genes for HbF regulation, develop prognostic guidelines and identify new therapeutic targets.

描述（由申请人提供）：地中海贫血是人类最常见的孟德尔特征。严重的-地中海贫血是由破坏或损害-珠蛋白基因表达的突变的复合杂合性或纯合性引起的。即使在具有相同的-地中海贫血突变的人群中，以及考虑到已知的上位性遗传因素（如-地中海贫血）时，疾病的严重程度也有很大差异。这种异质性大多与产生HbF的能力有关。我们假设，与γ -珠蛋白基因表达、红细胞内HbF浓度调节以及红细胞分化和增殖调控有关的顺式作用元件和反式作用因子存在遗传变异。我们希望确定这些基因变异。我们的第一个目标是通过研究30个家庭三联体，每个家庭有两个父母和一个孩子，在大约150个候选遗传位点中确定信息丰富的单核苷酸多态性（snp）和单倍型结构。利用在目标1中发现的单倍型标记snp，我们的第二个目标是通过研究约1000名β -地中海贫血携带者，发现与f细胞/HbF水平相关的遗传位点和基因。SNP和单倍型数据将用于f细胞/HbF数量性状位点（QTL）分析。第三个目标是通过研究大约320名严重的-地中海贫血患者，将与f细胞/HbF水平相关的遗传位点和基因与疾病表型联系起来。我们的长期目标是确定在HbF表达中重要的基因，并研究它们的生物学和病理生理功能。香港已建立足够规模的病人名册，以达致上述目标。我们已经形成了一个互动和有凝聚力的团队，由儿科医生、血液学家、遗传学家、分子生物学家、流行病学家、生物信息学家和统计学家组成，他们在拟议的临床/遗传方法方面经验丰富。这项研究的结果将使我们了解HbF调控的潜在重要基因的功能，制定预后指南并确定新的治疗靶点。