Genetic Modulation of HbF in Beta Thalassemia

描述(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β-地中海贫血是由取消或削弱β-珠蛋白基因表达的突变的复合杂合性或纯合性引起的。疾病的严重程度差别很大，即使在那些具有相同的β-地中海贫血突变的人中，当已知的上位性遗传因素，如阿尔法-地中海贫血被考虑在内。这种异质性大部分可以与生产HBF的能力有关。我们推测，与γ-珠蛋白基因表达有关的顺式作用元件和反式作用因子存在遗传变异，调节红细胞内HBF浓度，调节红系细胞的分化和增殖。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个三联体，每个家庭有2个父母和1个孩子，在大约150个候选遗传基因座上识别信息丰富的单核苷酸多态(SNPs)和单倍型结构。利用在Aim 1中发现的单倍型标签SNPs，我们的第二个目标是通过研究大约1,000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数量性状基因座(QTL)分析。第三个目标是通过研究大约320名严重的β-地中海贫血患者，将已发现的与F细胞/HBF水平相关的遗传基因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。香港已设立一个足够规模的病人登记册，以达到这些目标。我们已经形成了一支互动的、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，他们共同拥有拟议的临床/遗传方法方面的经验。这项研究的结果将为我们了解潜在的调节HBF的重要基因的功能，开发预后指南和确定新的治疗靶点做好准备。

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.