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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1682.)
© 2007 American Heart Association, Inc.

Editorials

Summary of the American Heart Association’s Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease

Donna K. Arnett for the Writing Group

From the Department of Epidemiology (D.K.A.), University of Alabama at Birmingham.

Correspondence to Dr Donna K. Arnett, University of Alabama at Birmingham, Department of Epidemiology, 1665 University Blvd, Birmingham, AL 35294. E-mail arnett{at}uab.edu

	Introduction

Top Introduction Three Examples of Genetically... Conclusions From Three Examples Current Areas of Focus... Recommendations for Future... References

 
Atherosclerotic cardiovascular disease (CVD) is a major health problem in the United States and around the world.^1,2 The development of CVD is a complex process, and evidence demonstrates that family history is associated with CVD.³ There are several mendelian disorders that contribute to CVD, and although the mutations are rare, they have a large relative risk. The most common forms of CVD, however, are believed to be multifactorial and to result from many genes, each with a small effect working alone or in combination with modifier genes or environmental factors.

See Circulation. 2007;115:2878–2901

Two main approaches have been used to discover genetic influences on CVD (Figure): genome-wide linkage and gene association studies. For discovery of new genes, the most frequently used method has been genome-wide linkage conducted using genetic and phenotypic data from families. Linkage analysis is a hypothesis-generating method intended to localize genomic regions that might contain genes influencing a trait. Once likely regions have been discovered, efforts shift to identifying the causative genes. Gene maps are scrutinized, and "candidate" genes within regions of interest are identified based on prior knowledge of gene function. Candidate gene association studies are designed to compare genotype frequencies between case and control groups; a statistical difference in frequencies between cases and controls offers evidence that a genotype is associated with the trait.

View larger version (50K): [in this window] [in a new window]   Figure. Fundamentals of the techniques used for the discovery of the genetic basis of CVD. Adapted with permission from: Arnett DK, Baird AE, Barkley RA, Basson CT, Boerwinkle E, Ganesh SK, Herrington DM, Hong Y, Jaquish C, McDermott DA, O’Donnell CJ. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2007;115:2878–2901. Copyright 2007 American Heart Association.

	Three Examples of Genetically Complex Forms of CVD

Top Introduction Three Examples of Genetically... Conclusions From Three Examples Current Areas of Focus... Recommendations for Future... References

 
Myocardial Infarction and Atherosclerotic CVD
Although there is no clear mendelian pattern of inheritance for myocardial infarction (MI) or atherosclerotic CVD, there is substantial evidence for a familial component to these diseases, particularly those with an early age of onset.^4–6 Evidence for linkage has been observed for chromosomes 1, 2, 3, 13, 14, 16, and X, although there has been no strong replication for any single chromosomal region.^7–14 Fine-scale linkage mapping identified a potentially causal gene, ALOX5AP, implicated in MI and stroke.¹² Although the evidence for linkage is not strong, the association of variants in the ALOX5AP locus with MI or stroke has been replicated in some studies.^15,16 Linkage studies have also been conducted for subclinical atherosclerotic CVD, although few studies have been reported.^17,18 A large number of candidate gene association studies have been conducted for MI and atherosclerotic CVD. However, there are relatively few gene associations that have been replicated.¹⁹ These studies have been summarized in recent reviews.^20,21 Variants of the APOE,²² PAI1,²³ ACE,²⁴ and MTHFR genes²⁵ have been examined in meta-analyses; overall, the magnitude of association for these common polymorphisms is modest.

Hypercholesterolemia and Other Lipid Phenotypes
Mendelian forms of hypercholesterolemia have been thoroughly studied, and a number are well documented. For example, familial hypercholesterolemia (FH) is the most common mendelian form of hypercholesterolemia. Caused by mutations in LDLR, FH causes elevated serum LDL-C. However, with prevalence for monogenic disorders ranging from 0.00002% to 0.2%, monogenic forms account for a fraction of observed hypercholesterolemia. Many linkage scans have sought genes with modest dyslipidemic effects, and several suggestive and significant regions have been implicated; however, causal genes remain elusive. Data for associations of dozens of gene variants with lipid related traits has been reviewed.²⁶ Of the many studies conducted, the most consistent evidence has been for the APOE gene.

Hypertension
Genetic factors account for approximately 30% of the population variability of blood pressure.²⁷ Several mendelian forms of hypertension have been identified.²⁸ For example, Liddle syndrome is a form of hypertension with increased activity of the amilioride-sensitive epithelial sodium channel attributable to mutations in the SCNN1B gene.²⁹ Because blood pressure is maintained by an intricate network of physiological systems, however, multiple genes and their interactions likely contribute to essential hypertension. There is suggestive linkage evidence for hypertension susceptibility genes spread across the genome. The Family Blood Pressure Program has conducted fine-scale linkage mapping and identified the SLC4A5 gene as an important candidate for hypertension.³⁰ Candidate gene association studies have served to connect specific genes with high blood pressure; however (as with the 2 other phenotypes), almost every published positive result has been followed by a negative result.³¹ Luft,³² Turner and Boerwinkle,³³ and Kaplan et al³⁴ have published reviews. Most of the candidate gene work related to hypertension has focused on various renal sodium transport proteins and members of the renin-angiotensin-aldosterone system (RAAS).³⁴ However, many complex interactions of the RAAS with other pathways and systems have yet to be elucidated.

	Conclusions From Three Examples

Top Introduction Three Examples of Genetically... Conclusions From Three Examples Current Areas of Focus... Recommendations for Future... References

 
Finding genes influencing MI, atherosclerotic CVD, lipids, and blood pressure through linkage and candidate gene studies has been somewhat successful. Future efforts will take advantage of the explosive growth in genomic resources and advanced statistical methods. Some of the inconsistency of findings observed across genetic and genomic studies of CVD is likely indicative of genetic heterogeneity of complex traits. Where gene-gene and gene-environment interactions exist, negative results may stem from genes whose relative phenotypic effects are smaller in the presence of specific genetic and environmental backgrounds.

	Current Areas of Focus for Genetics of CVD

Top Introduction Three Examples of Genetically... Conclusions From Three Examples Current Areas of Focus... Recommendations for Future... References

 
Gene-Environment Interaction
Gene-environment interaction occurs when the same genotype produces a different phenotype under different environmental exposures, such as age or a pharmacological treatment. Interventional studies can identify gene-environment interactions and provide evidence for translation of those findings into clinical practice. For example, blood pressure response to a low-sodium diet has been shown to vary by polymorphisms of AGT. Results from the Dietary Approaches to Stop Hypertension (DASH) Study showed the AGT –6 AA genotype is associated with a significant decrease in blood pressure for individuals on the DASH diet.³⁵ Similar approaches evaluating response to dietary fat intake³⁶ and physical activity³⁷ have demonstrated variable efficacy according to genotype, although a considerable amount of work remains to be done to elucidate both the genes and the optimal interventions to address the genetic risk.

Pharmacogenetics
Pharmacogenetics is the study of genetic determinants of individual variation in response to drugs. For example, CYP2D6 facilitates oxidative metabolism of CVD drugs, including flecainide, propafenone, and ß-blockers.^38–40 Depending on the population studied, 1% to 10% of subjects have a variant producing a rapid or extensive metabolizing phenotype. Other examples are documented.⁴¹ However, there is still a lack of research that provides the evidence to justify incorporation of pharmacogenetic testing into routine clinical practice. Given the large number of CVD drugs available and the large number of patients eligible to receive these drugs, even small variations in drug efficacy and safety have important implications for clinical and public health and, therefore, make such pharmacogenetic research potentially valuable.

Whole-Genome Association, Resequencing, and Expression Profiling Studies
Technological advances have led to development of low-cost dense genotyping arrays of 500000 or more single-nucleotide polymorphisms (SNPs) that cover the majority of the genome.⁴² For complex diseases, whole-genome association studies that type hundreds of thousands of variants provide excellent power, markedly exceeding the power of the linkage methodology, to identify genes of modest effect.⁴³ For example, a study of 100000 SNPs led to the discovery of a variant in the NOS1AP gene underlying QT-interval length on the ECG, a finding replicated in other cohorts.⁴⁴ Such studies provide proof of principle for the potential of whole-genome association studies for discovery of novel genetic determinants of CVD. A rapidly growing number of whole-genome association studies are now underway in disease-based case-control studies and large populations.

Whole-genome resequencing would resolve the question regarding the relative contribution of rare and common variants to common CVD. At present, whole-genome resequencing is prohibitively expensive.⁴⁵ However, several studies have performed focused resequencing of coding regions of candidate genes.^46,47 Such studies are laying the groundwork for far more extensive studies that may provide fully "personalized" characterization of an individual’s genome once costs are no longer prohibitively high.

Gene expression profiling creates a snapshot of the rate at which genes are expressed in a tissue sample. Because gene expression changes under pathological conditions, gene expression profiling can point to genes that may be involved in disease pathogenesis. For example, acute stroke was associated with upregulation of genes related to white blood cell activation and differentiation and with upregulation of genes in response to the altered cerebral microenvironment.⁴⁸ Gene expression profiling has potential application in clinical practice once specific molecular and clinically meaningful CVD signatures are developed.⁴⁹

Genetic Counseling
As DNA-based testing moves toward risk assessment and diagnosis in the clinic, the demand for genetic counseling is likely to grow. Although counseling for complex genetic diseases is still in the hypothetical stage, the discipline can draw from experiences with disorders such as familial hypercholesterolemia and venous thromboembolism to develop approaches for more genetically complex diseases. The guiding principles apposite in other testing and counseling contexts—such as restricting screening to high-risk individuals, concomitant assessment of nongenetic factors, and appropriate consideration for screening of family members—will also inform counseling practice for complex CVDs.

	Recommendations for Future Practice and Research

Top Introduction Three Examples of Genetically... Conclusions From Three Examples Current Areas of Focus... Recommendations for Future... References

 
We conclude this editorial with a set of recommendations intended to help incorporate knowledge into clinical and public health practice, foster and guide research, and prepare researchers and practitioners for changes likely to occur as molecular genetics moves from the laboratory to clinic.

• Continue to use family history as a tool to identify susceptible individuals and families.
  
• Develop a research infrastructure that includes the following:

       Incentives for researchers to assemble multidisciplinary collaborative research teams.
  

       Incentives for researchers who are not currently conducting genetic research to collect DNA and consent to use specimens and data in future studies.
  

       Incentives for researchers to undertake translational research.
  

       Public-private partnerships that expedite the translation of genetic/genomic findings to clinical and public health practice.
  

  
  
• Prioritize the following research agendas:

       Characterize genetic variants that are associated with CVD across individuals, communities, and populations.
  

       Evaluate how behavioral and environmental factors interact with genes to influence CVD risk.
  

       Develop new technologies in CVD characterization, risk assessment, and outcome prediction.
  

       Assess gene-drug interaction and the impact of these findings on intervention strategies and drug development.
  

       Develop new methods to analyze and understand the wealth, breadth, and complexity of genetic data.
  

  
  
• Prepare proactively for effective genetic screening programs

       Establish prevalence criteria to trigger screening programs in at-risk populations.
  

       Create standards and laboratory oversight mechanisms for genetic testing facilities.
  

       Match appropriate treatment guidelines to particular genetic susceptibility findings.
  

       Assess the potential cost effectiveness of genetic screening programs.
  

  
  
• Educate researchers, clinicians, public health professionals, and the general public.

       Effective researchers must be proficient in genetic epidemiology, computational biology, and statistical genetics.
  

       Clinicians should become aware of the genetic tools at their disposal and understand and put to use the results of genetic screening for complex CVDs, and graduate educational curricula should include population biology and genetics.
  

       Public health professionals must continue to incorporate genetic knowledge into their understanding of population risk of CVDs.
  

       The general public will need a basic genetic literacy to understand the technical and negotiate the ethical aspects of molecular genetic screening.
  

  
  

	Acknowledgments

 
Disclosures

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View this table: [in this window] [in a new window]   Reviewer Disclosures

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