Reviews of Translational Medicine and Genomics in Cardiovascular Disease:
Reviews of Translational Medicine and Genomics in Cardiovascular Disease:
The enduring subdivision of cardiomyopathies into hypertrophic (HCM), dilated (DCM), and restrictive (RCM) categories reflects the emphasis of traditional classifications on morphology. Rapid advances in the genetic interrogation of these disorders have redefined their taxonomy and revealed potential conflicts between the old and new classifications. Hypertrophic cardiomyopathy has been redefined as a disease of perturbed sarcomere function. Dilated cardiomyopathy is a disease that results from more varied perturbations, including, but not limited to, defects of the cytoskeleton. Positional cloning and candidate gene approaches have been successful in identifying < 40 disease loci, many of which have led to disease genes in HCM, DCM, RCM, and arrhythmogenic right ventricular cardiomyopathy. These findings provide mechanistic insights, permit genetic screening, and to a limited extent, facilitate prognostication. Although single gene analyses rapidly focus down to the underlying mechanistic pathways, they do not take account of all relevant variation in the human genome. Correspondingly, advances in genomics, through microarrays, have facilitated characterization of these broader downstream elements. As well as refining the taxonomic reclassification of cardiomyopathies, these genomic approaches, coupled with functional studies, have identified novel potential therapeutic targets, such as cardiac energetics, calcium handling, and apoptosis. We review the successes and pitfalls of genetic and genomic approaches to cardiomyopathy and their impact on current and future clinical care.(J Am Coll Cardiol 2007; 49:1251-64) © 2007 by the American College of Cardiology Foundation
One hundred fifty years since Mendel's breeding experiments, 50 years since the discovery of the structure of deoxyribonucleic acid by Watson and Crick, and 5 years from the publication of the human genome draft, the unprecedented pace of technologic progress has inspired awe and built up expectations that genetics and genomics will provide radical insights into disease. In inherited single gene disorders, and in the relatively simple somatic genetics of cancer, important mechanistic insights have been afforded, leading to improved diagnosis, screening, and prognosis. Genomic tools have honed stratification (e.g., by the use of array technology in leukemia, breast cancer, melanoma), and some therapeutics have been personalized (e.g., gefitinib in lung cancer).
Cardiovascular disease is the leading cause of illness and death worldwide, with an estimated 1 million deaths annually in the U.S. alone (≈ 40% of all-cause mortality). Specifically, heart failure has a prevalence of ≈ 2% with an annual U.S. mortality of ≈ 300,000 and an annual cost of $17 billion. Most of the burden of cardiovascular disease has complex genetic and environmental origins and is only now becoming amenable to large-scale genetic analyses. Preliminary findings are beginning to indicate the potential of genetic dissection of common cardiovascular diseases (e.g., the identification of ALOX5AP mutations that modify leukotriene B4 metabolism and are associated with myocardial infarction and stroke). But progress sufficient to already be clinically relevant has largely been confined to the less common monogenic forms of the various cardiovascular pathologies: contributions to lipid disorders (e.g., low-density lipoprotein receptor mutations in familial hypercholesterolemia), hypertension (e.g., epithelial Na channel, ENaC, mutations in Liddle's syndrome), cardiomyopathies, and channelopathies. In the present review, we highlight the successes and pitfalls of genomic approaches to disease-gene, susceptibility-gene, and pathway discovery using the cardiomyopathies as our model. The cardiomyopathies were the first primary cardiac disorders to be understood at the molecular level, offering the potential for improved treatment strategies not only for patients with cardiomyopathies but also for heart failure in general.
The enduring subdivision of cardiomyopathies into hypertrophic (HCM), dilated (DCM), and restrictive (RCM) categories reflects the emphasis of traditional classifications on morphology. Rapid advances in the genetic interrogation of these disorders have redefined their taxonomy and revealed potential conflicts between the old and new classifications. Hypertrophic cardiomyopathy has been redefined as a disease of perturbed sarcomere function. Dilated cardiomyopathy is a disease that results from more varied perturbations, including, but not limited to, defects of the cytoskeleton. Positional cloning and candidate gene approaches have been successful in identifying < 40 disease loci, many of which have led to disease genes in HCM, DCM, RCM, and arrhythmogenic right ventricular cardiomyopathy. These findings provide mechanistic insights, permit genetic screening, and to a limited extent, facilitate prognostication. Although single gene analyses rapidly focus down to the underlying mechanistic pathways, they do not take account of all relevant variation in the human genome. Correspondingly, advances in genomics, through microarrays, have facilitated characterization of these broader downstream elements. As well as refining the taxonomic reclassification of cardiomyopathies, these genomic approaches, coupled with functional studies, have identified novel potential therapeutic targets, such as cardiac energetics, calcium handling, and apoptosis. We review the successes and pitfalls of genetic and genomic approaches to cardiomyopathy and their impact on current and future clinical care.(J Am Coll Cardiol 2007; 49:1251-64) © 2007 by the American College of Cardiology Foundation
One hundred fifty years since Mendel's breeding experiments, 50 years since the discovery of the structure of deoxyribonucleic acid by Watson and Crick, and 5 years from the publication of the human genome draft, the unprecedented pace of technologic progress has inspired awe and built up expectations that genetics and genomics will provide radical insights into disease. In inherited single gene disorders, and in the relatively simple somatic genetics of cancer, important mechanistic insights have been afforded, leading to improved diagnosis, screening, and prognosis. Genomic tools have honed stratification (e.g., by the use of array technology in leukemia, breast cancer, melanoma), and some therapeutics have been personalized (e.g., gefitinib in lung cancer).
Cardiovascular disease is the leading cause of illness and death worldwide, with an estimated 1 million deaths annually in the U.S. alone (≈ 40% of all-cause mortality). Specifically, heart failure has a prevalence of ≈ 2% with an annual U.S. mortality of ≈ 300,000 and an annual cost of $17 billion. Most of the burden of cardiovascular disease has complex genetic and environmental origins and is only now becoming amenable to large-scale genetic analyses. Preliminary findings are beginning to indicate the potential of genetic dissection of common cardiovascular diseases (e.g., the identification of ALOX5AP mutations that modify leukotriene B4 metabolism and are associated with myocardial infarction and stroke). But progress sufficient to already be clinically relevant has largely been confined to the less common monogenic forms of the various cardiovascular pathologies: contributions to lipid disorders (e.g., low-density lipoprotein receptor mutations in familial hypercholesterolemia), hypertension (e.g., epithelial Na channel, ENaC, mutations in Liddle's syndrome), cardiomyopathies, and channelopathies. In the present review, we highlight the successes and pitfalls of genomic approaches to disease-gene, susceptibility-gene, and pathway discovery using the cardiomyopathies as our model. The cardiomyopathies were the first primary cardiac disorders to be understood at the molecular level, offering the potential for improved treatment strategies not only for patients with cardiomyopathies but also for heart failure in general.
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