The Effect of HapMap on Cardiovascular Research and Clinical Practice
The Effect of HapMap on Cardiovascular Research and Clinical Practice
The Haplotype Genetic Map (HapMap) is an invaluable resource to the cardiovascular researcher, enabling a decrease in cost and an increase in the efficiency and speed of discoveries in the laboratory. As cardiologists, we need to understand the vocabulary of genomics because the translation of scientific findings using HapMap could provide insight for improved care and therapeutic guidance of our patients. Genomics is the evaluation of genes as a dynamic system, in which genes interact to influence biologic pathways, networks and physiology. The HapMap promises to increase the efficiency of genomics in identifying cardiovascular-disease-related genes that could become vital for choosing relevant tests and providing preventative and curative therapies. In this Review, the HapMap will be described, to provide insight into the relevance of this work to cardiovascular practice, to clinical research in cardiovascular disease and to future discoveries in diagnostic and therapeutic modalities.
One person, trillions of cells, 23 pairs of chromosomes, 30,000 genes, 3,164,700,000 base pairs -- the complexity is astounding. From taking months or years to identify and sequence a single gene, we have made leaps and bounds and now use DNA chips to identify up to 500,000 genetic markers in just a few days. Despite the dramatic improvement in processing time, the genetic variations responsible for many of the common cardiovascular diseases have remained elusive. The Haplotype Genetic Map (HapMap) has recently been published, however, adding to researchers' armamentarium by providing an invaluable resource to increase the efficiency, decrease the cost and increase the speed of our genetic discoveries in the laboratory. What does this development mean for our cardiovascular practice? Will the HapMap change the way we prescribe and use medications and how we choose devices in the catheterization laboratory, as well as improve patient outcome? The answer to all these questions is probably yes, and these changes will be seen in the near future with the advent of the genetic revolution. Genomics is the evaluation of genes as a dynamic system, in which genes interact to influence biologic pathways, networks and physiology. To take full advantage of the HapMap, we need to learn the language, understand the implications and develop unambiguous phenotypes for common clinical disorders.
Practicing cardiologists regularly face clinical scenarios that are likely to have a strong genetic origin, but for which the molecular basis has not yet been determined. For example, patients who undergo successful angioplasty and stent implantation, performed by the best interventional cardiologists with diligent attention paid to mechanical and pharmacologic details, continue to endure the risk of in-stent restenosis and subacute thrombosis. Candidate gene testing of the genes most likely to be involved has provided some clues to the etiology of in-stent restenosis and subacute thrombosis, but has provided a less-than-complete picture of the multivariable process. Phenotypes are, by definition, the expression of specific traits and are based on genetic and environmental influences. Biological variables, such as platelet reactivity, pharmacologic resistance and cellular proliferation, that determine complex disease phenotypes, such as subacute thrombosis and restenosis, are intertwined with environmental variables, such as diet, lifestyle, age, sex and risk-factor therapies. This interplay makes it difficult to identify causative genes. One hypothesis for the presence of such common but complex disease phenotypes is that they are caused by multiple common genetic variants working in concert with environmental factors. Only by elucidating the complex interactions of such genetic variants, which are weak individually but together confer a deleterious phenotype, will we begin to understand and treat or prevent effectively processes such as in-stent restenosis and subacute thrombosis.
The identification of these common variants is precisely where the HapMap promises to be a key resource. Most breakthroughs in genetics have been made through linkage studies performed in rarer, more severe, single-gene Mendelian diseases. In common complex diseases a number of genetic variants are expected to underlie the clinical phenotype. The synergistic effects of multiple genetic variants, along with environmental factors that act synergistically to develop the phenotype, make it more difficult to identify the actual causative genetic variants. Classic case-control association studies using the HapMap could provide the experimental design to circumvent this difficulty. In this Review, we examine the HapMap and provide insight into the relevance of this work to cardiovascular practice, clinical research in cardiovascular disease and future discoveries in diagnostic and therapeutic modalities.
Summary and Introduction
Summary
The Haplotype Genetic Map (HapMap) is an invaluable resource to the cardiovascular researcher, enabling a decrease in cost and an increase in the efficiency and speed of discoveries in the laboratory. As cardiologists, we need to understand the vocabulary of genomics because the translation of scientific findings using HapMap could provide insight for improved care and therapeutic guidance of our patients. Genomics is the evaluation of genes as a dynamic system, in which genes interact to influence biologic pathways, networks and physiology. The HapMap promises to increase the efficiency of genomics in identifying cardiovascular-disease-related genes that could become vital for choosing relevant tests and providing preventative and curative therapies. In this Review, the HapMap will be described, to provide insight into the relevance of this work to cardiovascular practice, to clinical research in cardiovascular disease and to future discoveries in diagnostic and therapeutic modalities.
Introduction
One person, trillions of cells, 23 pairs of chromosomes, 30,000 genes, 3,164,700,000 base pairs -- the complexity is astounding. From taking months or years to identify and sequence a single gene, we have made leaps and bounds and now use DNA chips to identify up to 500,000 genetic markers in just a few days. Despite the dramatic improvement in processing time, the genetic variations responsible for many of the common cardiovascular diseases have remained elusive. The Haplotype Genetic Map (HapMap) has recently been published, however, adding to researchers' armamentarium by providing an invaluable resource to increase the efficiency, decrease the cost and increase the speed of our genetic discoveries in the laboratory. What does this development mean for our cardiovascular practice? Will the HapMap change the way we prescribe and use medications and how we choose devices in the catheterization laboratory, as well as improve patient outcome? The answer to all these questions is probably yes, and these changes will be seen in the near future with the advent of the genetic revolution. Genomics is the evaluation of genes as a dynamic system, in which genes interact to influence biologic pathways, networks and physiology. To take full advantage of the HapMap, we need to learn the language, understand the implications and develop unambiguous phenotypes for common clinical disorders.
Practicing cardiologists regularly face clinical scenarios that are likely to have a strong genetic origin, but for which the molecular basis has not yet been determined. For example, patients who undergo successful angioplasty and stent implantation, performed by the best interventional cardiologists with diligent attention paid to mechanical and pharmacologic details, continue to endure the risk of in-stent restenosis and subacute thrombosis. Candidate gene testing of the genes most likely to be involved has provided some clues to the etiology of in-stent restenosis and subacute thrombosis, but has provided a less-than-complete picture of the multivariable process. Phenotypes are, by definition, the expression of specific traits and are based on genetic and environmental influences. Biological variables, such as platelet reactivity, pharmacologic resistance and cellular proliferation, that determine complex disease phenotypes, such as subacute thrombosis and restenosis, are intertwined with environmental variables, such as diet, lifestyle, age, sex and risk-factor therapies. This interplay makes it difficult to identify causative genes. One hypothesis for the presence of such common but complex disease phenotypes is that they are caused by multiple common genetic variants working in concert with environmental factors. Only by elucidating the complex interactions of such genetic variants, which are weak individually but together confer a deleterious phenotype, will we begin to understand and treat or prevent effectively processes such as in-stent restenosis and subacute thrombosis.
The identification of these common variants is precisely where the HapMap promises to be a key resource. Most breakthroughs in genetics have been made through linkage studies performed in rarer, more severe, single-gene Mendelian diseases. In common complex diseases a number of genetic variants are expected to underlie the clinical phenotype. The synergistic effects of multiple genetic variants, along with environmental factors that act synergistically to develop the phenotype, make it more difficult to identify the actual causative genetic variants. Classic case-control association studies using the HapMap could provide the experimental design to circumvent this difficulty. In this Review, we examine the HapMap and provide insight into the relevance of this work to cardiovascular practice, clinical research in cardiovascular disease and future discoveries in diagnostic and therapeutic modalities.
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