Genetics in heart failure: Practical incorporation of this new biologic dimension☆
Article Outline
- Abstract
- Clinical application of genetic information
- The importance of phenotype
- Identifying disease genes
- Genetic contribution to disease
- Clinical use
- Acknowledgements
- References
- Copyright
Abstract
Am Heart J 2002;144:938-40.
See related article on page 1081.
Clinical application of genetic information
As the results of the Human Genome Project unfold, numerous predictions of its impact have been made. These range from patients having individualized genetic drug profiles to gene therapy reprogramming of dysfunctional organs. The inevitable hype that surrounds such scientific breakthroughs must be viewed in light of the tasks to be accomplished to make these dreams a reality. Current estimates place the number of genes in the human genome at a surprisingly low 30,000 to 40,000, but with substantial posttranscriptional complexity. The Human Genome Project, at its core, is a vast amount of information about gene location and sequence. The ultimate role of each gene within human physiology and pathophysiology for most of the genome remains to be defined. To determine the functional continuum from cellular physiology to the integrated biology of the patient for each gene will require a new paradigm of investigation. Such research must also take into account the physiologic effects of genetic variation within each gene. Being armed with the knowledge of the function of each gene and its variations will provide the genomic template on which to substantially advance clinical medicine.
In this issue of the Journal, Hershberger et al1 identify a novel mutation of the lamin A/C gene in a family with dilated cardiomyopathy, clinically pertinent conduction system disease, and the need for permanent pacemaker implantation. This study is an example of the work currently being done on the genetics of cardiomyopathies. Lamin A/C is a nuclear membrane protein that has been implicated in familial dilated cardiomyopathy and conduction system disease.2 Hershberger et al identified a family of individuals with both dilated cardiomyopathy and conduction system disease. This clinical presentation was similar to those previously observed in familial cardiomyopathies associated with mutations in the lamin A/C gene. Given this historical background, the lamin A/C gene was selected as a reasonable candidate gene to search for a mutation to account for this clinical entity. Sequencing the index case revealed a novel alteration of a single nucleotide within the lamin A/C gene, a single nucleotide polymorphism. This same mutation was then found in a majority of the affected family members in the pedigree. This study reinforces the importance of cytoskeletal proteins in dilated cardiomyopathy. It also provides the basis for discussing issues confronting the medical community in incorporating this genomic dimension into the understanding and treatment of disease. These considerations include the careful clinical characterization of the underlying disease, the isolation of the contributing genetic factors, and the hurdle of statistically testing this information to allow clinical application of findings.
The importance of phenotype
The initial step in addressing the genetics of a disease is to develop a clear characterization of the disease. A common term in this context is “phenotype,” which simply refers to the observable traits or, in medical terms, observable clinical characteristics. The importance of clear and objective characterization of clinical features into pathophysiologically relevant patterns may seem obvious, but it serves as the foundation for making clinically pertinent genetic associations. The original use of phenotype was to group individuals in such a way as to study the transmission of traits. Mendelian inheritance includes classically described autosomal dominant and autosomal recessive disorders, where the analysis and establishment of transmission patterns is straightforward. In cardiovascular medicine, such inheritance patterns can be observed in familial cardiomyopathies and familial hyperlipidemias. Common diseases, such as atherosclerosis, are generally complex diseases that have both multiple genes and gene-environment interactions as contributors to the development, presentation, or severity of the disease process. Multiple genes may contribute in an incremental or combinatorial fashion. The spectrum with which complex diseases appear and run their clinical course could, to some degree, be explained by the summation of contributing genes.
Clinicians commonly observe such spectrums in the development and course of common diseases. For example, 2 patients with ischemic cardiomyopathy, anterior infarcts, and identical left ventricular ejection fractions can have very different clinical presentations and outcomes. Their symptoms, exercise capacity, and mortality can vary, with little apparent difference in physiologic substrate. We know that comorbidities, such as diabetes and mitral insufficiency, alter clinical outcome.3, 4 Meticulous characterization of disease into such patterns of outcome is fundamental to successful genetic association studies.
Identifying disease genes
In their study, Hershberger et al use a common approach to identifying the association between gene and the disease phenotype. With prior knowledge of the literature, they focused on a gene known to be associated with familial dilated cardiomyopathy and conduction system disease. This approach, whereby one selects a gene for investigation with regard to a phenotype, is termed a “candidate gene approach.” The assumption—based on knowledge from the existing literature or plausible biological involvement with the disease process—is that the candidate gene has a relationship to the disease of interest. Other approaches do not focus on a prior relationship. These approaches do not assume any prior knowledge of the type, location, or product of the involved gene. Examples of such approaches are linkage studies and expression analyses.
Linkage analysis uses the principle that chromosomal regions close to each other tend to be coinherited to identify genetic markers of the disease in question. The inheritance of well-spaced markers (stretches of DNA) within the entire genome are investigated (in pedigrees or by case-control studies) to isolate regions in the genome with a statistical association with the inherited disease. Markers with a high degree of linkage locate the gene's region. In reality, however, the marker gene may be far away from the gene of interest, as far away as millions of base pairs. Genes known to be within that region are then investigated to find a mutation that can explain the specific phenotype.
Examination of the relationship of gene products—mRNA or protein— with disease can also help isolate genes of interest. Those mRNA and protein levels that are altered in the diseased tissue compared with normal tissue are considered potentially active in contributing to the disease state, although they may also be epiphenomena.
Genetic contribution to disease
The genetic contributions to heart failure can be broadly grouped into causative and modifier genes. Numerous components of the cytoskeletal system have been implicated as genes that cause dilated cardiomyopathy. In contrast, modifier genes become active after the disease is present and thus influence clinical course. As an example, in the presence of pre-existing cardiomyopathy, a particular β2 receptor genetic variant is associated with both poorer exercise tolerance and lower transplant-free survival.5, 6 Other allelic variants such as the adenosine monophosphate deaminase-1 gene and an endothelin-A polymorphism have been implicated as well.7, 8 Modifier genes are identified in a similar fashion to that of causative genes. Investigations to date have often identified these genes through a candidate gene approach. The β-adrenergic system and the endothelin system are well known neurohormonal players in the syndrome of heart failure and have been targeted for therapeutic interventions. Thus, it is only natural that genes of the receptors for these ligands might be considered reasonable candidate genes. The neurohormonal system is only 1 of several systems under intensive investigation in studies of heart failure genetics. Others include those of the inflammatory system and excitation-contraction coupling.
Clinical use
Once genetic variants are associated with the disease, they are studied for their potential use as markers of susceptibility, prognosis, or diagnosis. They also could be helpful in selecting therapies, either by identifying patients at particular risk of side effects or in need of special dosing (the growing field of pharmacogenomics).
The promise that genetic profiling may translate into identifying subsets of patients who may derive particular benefit from a new therapy must be tempered by the reality of the challenge of demonstrating such a finding. As an example, assume that a drug results in a 25% relative risk reduction in heart failure mortality. A trial of patients with a 30% mortality designed with 90% power to detect this 25% relative risk reduction (α = .05) would require approximately 1500 patients. Let us assume that there are 2 gene variants (variants A and a). Variant A is the wild type in a population and occurs at a frequency of 80%, whereas variant a occurs at a frequency of 20%. Variant a results in 50% greater treatment effect than variant A. To have adequate power to determine this difference in treatment effect according to genotype, approximately 20 times the original sample size, or 30,000 patients, would be needed. The ability to examine multiple gene variants with treatment effect simultaneously would require enormous numbers of patients. Therefore, pharmacogenomics aimed at identifying patients with varying degrees of treatment response will require a new paradigm of clinical trials scope.
Beyond these considerations lies another question: what are the clinical implications for heart failure that genetics has provided us to date? Identification of genetic causes of disease is anticipated to be helpful in targeting therapies; however, the etiology of a clinical syndrome does not necessarily predict treatment response. For example, cardiomyopathies with either ischemic or nonischemic etiology have a similar beneficial response to common heart failure therapies such as β-blockers and angiotensin-converting enzyme inhibitors. Moreover, the discoveries of genetic mutations and their associations with hypertrophic and idiopathic cardiomyopathies have not yet lead to any clinical applications. The association of certain cytoskeletal gene variants and dilated cardiomyopathy may help our understanding of mechanisms and eventually lead to targeted therapeutics. The promise that unraveling the relationships between gene variation, gene expression, and disease will revolutionize basic understanding of disease has led to enthusiasm for the impact of genomic understanding of heart disease. This enthusiasm must be tempered by the practical reality that use of genetic information at the bedside to improve patient outcomes is many years away. Extensive collaboration will be necessary for these efforts to be successful. Along with the identification of genes, there must be meticulous characterization of each gene's function and the assembly of large databases to couple clinical patterns and genetic information. This monumental task confronts those in the field and will require new paradigms of research. There has never been a period of such potential in medicine and, at the same time, such complexity.
Acknowledgements
We thank Andrew Allen, PhD for assistance with the power calculations.
References
- A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J. 2002;144:1081–1086
- Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction system disease. N Engl J Med. 1999;341:1715–1724
- Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of the left ventricular systolic dysfunction. J Am Coll Cardiol. 2001;38:421–428
- Mitral regurgitation as an independent risk factor for mortality in patients with heart failure and left ventricular systolic dysfunction [abstract]. J Am Coll Cardiol. 2002;39(A Suppl):194A
- The Ile164 beta-2 adrenergic polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534–1539
- Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res. 2000;86:834–840
- Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation. 1999;99:1422–1425
- A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2001;22:1948–1953
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PII: S0002-8703(02)00217-X
doi:10.1067/mhj.2002.126738
© 2002 Mosby, Inc. All rights reserved.
Refers to article:
- A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation
