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.
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