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Regulatory Gene Mutations Affecting Apolipoprotein Gene Expression: Functions and Regulatory Behavior of Known Genes May Guide Future Pharmacogenomic Approaches to Therapy
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Vassilis I. Zannis
Published/Copyright:
June 1, 2005
Abstract
A pharmacogenomic approach to therapy requires systematic knowledge of the regulatory regions of the genes, as well as basic understanding of transcriptional regulatory mechanisms of genes. Using the apolipoprotein (apo) A-I/CIII gene cluster as a model system, we have identified by in vitro and in vivo studies the regulatory elements and the factors which control its transcription. Studies in transgenic mice established that the hepatocyte nuclear factor (HNF-4) binding site of the apoCIII enhancer, which controls transcription of both genes, is required for the intestinal expression of apoA-I and apoCIII genes, and enhances synergistically their hepatic transcription in vivo. The three Sp1 sites of the enhancer are also required for the intestinal expression of apoA-I and apoCIII genes in vivo, and for the enhancement of the hepatic transcription. The regulation of the apoE/apoCI/apoCIV/apoCII cluster is also cited. It is expected that identification of the regulatory regions of genes will be soon accelerated by the sequencing of several mammalian genomes. The functional analyses of the regulatory domains of genes involved in lipid homeostasis, combined with cross-species sequence comparisons in the near future, may identify natural regulatory gene polymorphisms in the general population that will permit rational pharmacogenomic approaches for treatment of dyslipidemias.
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Published Online: 2005-06-01
Published in Print: 2003-04-25
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- First Santorini Conference: From Genetic Variations to Risk Prediction and Pharmacogenomics
- Pharmacogenetics and Pharmacogenomics in Drug Discovery and Development: An Overview
- Regulatory Gene Mutations Affecting Apolipoprotein Gene Expression: Functions and Regulatory Behavior of Known Genes May Guide Future Pharmacogenomic Approaches to Therapy
- The Proteome: Anno Domini 2002
- Cardiac Sodium Channel Diseases
- Haemophilia B: From Molecular Diagnosis to Gene Therapy
- The Use of Denaturing High-Performance Liquid Chromatography (DHPLC) for the Analysis of Genetic Variations: Impact for Diagnostics and Pharmacogenetics
- Molecular Diagnostics by Microelectronic Microchips
- Molecular Beacons as Diagnostic Tools: Technology and Applications
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- Comparison of Standard PCR and the LightCycler® Technique to Determine the Thrombophilic Mutations: An Efficiency and Cost Study
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- The –308 G/A Tumor Necrosis Factor-α Gene Dimorphism: A Risk Factor for Unstable Angina
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