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Utility of genetic approaches to common cardiovascular diseases

2001; American Physical Society; Volume: 281; Issue: 1 Linguagem: Inglês

10.1152/ajpheart.2001.281.1.h1

1522-1539

Stephen Harrap, Steven Petrou,

Genetic Associations and Epidemiology

EDITORIALUtility of genetic approaches to common cardiovascular diseasesStephen B. Harrap, and Steven PetrouStephen B. Harrap Department of Physiology, Victorian Physiological Genomics Centre, The University of Melbourne, Victoria 3010, Australia, and Steven Petrou Department of Physiology, Victorian Physiological Genomics Centre, The University of Melbourne, Victoria 3010, AustraliaPublished Online:01 Jul 2001https://doi.org/10.1152/ajpheart.2001.281.1.H1MoreSectionsPDF (137 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat HANDS UP FOR GENETICSThe title of this editorial was the topic for an intended debate at a celebration to mark the retirement of Colin Johnston (15). Two other debate topics entitled "That Clinical Trials Have Had Their Day" and "That 140/85 is Low Enough" were embraced enthusiastically by the delegates and provided entertaining and stimulating repartee. However, the genetics topic never saw the light of day because too few were willing to stand and defend genetics and where it is taking us. Why were the attendant cardiovascular scientists and clinicians so lukewarm about genetics? How does this gel with the multimillion dollar investments by government and industry into genetics of common disease, in particular cardiovascular disease? Are clinicians simply philistines in a postgenomics culture? Has genetics failed to explain itself clearly and justifiably? Is it leading us up the wrong path to frustrating conclusions?The potential gulf between what is happening in genetics laboratories and in the "real world" of health care is a concern. On one side, genetics is trying to live up to a remarkable potential, including improvements in prevention and diagnosis and treatment of common conditions such as coronary disease, stroke, and cancer. On the other, a misunderstanding of what genetics can offer is fueling unrealistic expectations. The confusion between expectation and reality is exacerbated by ever-changing technological wizardry.The apparent medical skepticism about where genetics is taking us deserves some consideration. A relevant cardiovascular genetic example is the angiotensin-converting enzyme (ACE) gene.THE RISE AND FALL OF THE ACE GENEA vivid memory from 1991 is of a young postdoctoral scientist running breathless into the lab announcing that the "gene for hypertension" had been discovered. He was referring to two papers published almost simultaneously that reported results of the first genome-wide searches for chromosomal locations of genes that might explain high blood pressure in rats. His excitement was in part generated by the fact that there was obviously an international race in which the first two place-getters published in Cell(18) and Nature (16). It was also exciting because as unbiased searches of the genome, the results might represent a genetic truth. The "truth" related to a region on rat chromosome 10 that encompassed the ACE gene. There was no evidence that the ACE gene was the culprit. It could have one of hundreds of genes in the region.However, despite the carefully worded texts of both papers, the ACE gene stole the limelight. After all, the renin-angiotensin system had a strong physiological and therapeutic pedigree in blood pressure, and the renin gene had been implicated in rat hypertension 2 years earlier (37). In cardiovascular medicine, ACE inhibitors were establishing an enviable reputation in a growing range of clinical conditions. By the time the results filtered through to clinical realms, their message had taken on strange forms. A clinical colleague remarked at the time that he understood that the "ACE inhibitor gene" had been shown to cause hypertension!Attention soon turned to humans, as polymorphic markers were available for the human ACE gene. Excitement built as first in hypertension (52) and then in the cardiovascular Holy Grail of myocardial infarction, the ACE gene was implicated. In a landmarkNature paper (9), the ACE D allele was not only associated with heart attack but also anointed as a "potent risk factor." This seemed to vindicate the concept that genetics could reveal fundamental causes of common disease. In reality, the DD genotype frequency was found in 32% of heart attack victims and 27% of unaffected controls; a small difference that would not satisfy the predictive requirements of a useful cardiovascular risk factor. Nevertheless, it was surely only a matter of time before the tests could be refined.The implications were clear; tests of individual genetic composition might tell us something about disease risk. Clinicians embraced the concept of "genetic risk factors," which was reinforced by subsequent high profile cardiovascular discoveries concerning other genes in the renin-angiotensin system including angiotensinogen (19, 20) and the AT1 receptor (46). Some results (6) even stimulated discussion of preclinical diagnosis in children. It was no coincidence that pharmaceutical industry investment priorities and the smart money in the market were swinging toward genetics (4).Meanwhile, the ACE gene momentum was fueled by the ever-expanding list of associated conditions, facilitated by the relative simplicity of the genetic tests (31). Like wildfire, the apparent influence of the ACE gene spread from cardiovascular disease to renal disease (51), to diabetes (27), to respiratory disease (7), to autoimmune disease (35), to hematological disease (34), to mental health (5), to dementia (3), and even to athletic prowess (28).It is interesting to track the MEDLINE citations from 1990–2000 of the papers that contain the words "ACE gene." It reveals an increase from 2 papers in 1990 to a peak of 103 papers in 1998. The vast majority were tests of association between the originally described dimorphic marker and some clinical condition or complication. Research titles implied genetic causation with phrases such as "effects of," "influence of," and "contribution of" the ACE genotype. The path to diagnostic tests, however unfounded, was being laid before us by genetics. Some clinicians were starting to wonder whether they should take advantage of commercial genetic testing that was starting to appear in the advertising pages of some of their reading material and the internet (30a).Physiological issues seemed superfluous now that genetic markers could bypass all those annoying biological variables to get to the root of the disease process. Authors often used physiological concepts to bridge the gaps between the ACE gene and the disease. Yet few attempted to define the underlying physiological effects of the DNA variant (29, 32). Even after a decade, the depth of understanding has not progressed far beyond the early observations that the ACED allele was associated with increased ACE activity (40, 47). The fact that ACE is not generally a rate-limiting step in the formation of angiotensin II and theD allele could not be linked with high angiotensin II levels (14, 22) was rarely mentioned.The building excitement about ACE gene cardiovascular diagnosis and risk assessment began to subside as negative studies appeared. Of those published (and many more unpublished), some were dismissed, as under powered or ill designed, but large and careful studies (2, 25,26, 36) were more difficult to ignore. As is the fashion, reviews of published works were presented as meta analyses in an attempt to rationalize the differences by combining them (1, 13,41, 43, 44). The outcomes were sometimes mathematical estimates that belonged in the twilight zone. Editorials started to sound doubtful (24, 45). Although the explanations for the discrepancies were not immediately obvious, one thing was clear. The ACE gene was not a reliable marker of cardiovascular risk.No wonder clinicians might feel that they had been lead up the garden path. The unfolding sequence over the last decade of yes, no, and then maybe left many wondering what had happened to the new genetic risk factors that were going to revolutionize diagnostic and treatment decisions?FROM GENES TO THE GENOMESAs research shifts gear from genes to the entire genome, can we learn anything from the last decade and avoid making similarly frustrating journeys up garden paths? Our knowledge of the 3 billion base pairs and the ability to interrogate every inch of human DNA is exciting indeed and brings great possibilities. But is the logical end point a comprehensive suite of molecular markers for genetic diagnosis and prognosis?On June 26, 2000, President Clinton congratulated scientists on the completion of the first survey of the entire human genome and stated that the working draft of the human genome could be used to alert patients that they are at risk for certain diseases, reliably predict the course of disease, precisely diagnose disease, and ensure the most effective treatment is used and develop new treatments at the molecular level. At the subsequent press briefing Dr. Francis Collins (Director of the National Human Genome Research Institute) said, "I would be willing to make a prediction that within 10 years, we will have the potential of offering any of you the opportunity to find out what particular genetic conditions you may be at increased risk for based upon the discovery of genes involved in common illnesses like diabetes, hypertension, heart disease, and so on."Such statements received international attention and were remarkably explicit. They set timeframes, nominated diseases, and pointed directly toward genomic discovery being used to develop precise and reliable genetic testing for individuals. But is it plausible to envisage genome screening available to everyone or in doing so is genetics building a garden path of the "superhighway" variety?THE CHALLENGE OF COMMON DISEASESOne imagines that it was not by accident that Dr. Collins nominated diabetes, hypertension, and heart disease. These conditions are examples of the major causes of morbidity and mortality. For example, in terms of international disease burden, ischemic heart disease and cerebrovascular disease are expected to be ranked 1 and 4 by the year 2020 (30). They also represent the most difficult challenges for genetics. Each is believed to be polygenic, resulting from the accumulation and combination of a number of incremental genetic risks (polygenes). The expression of these risks depends on interaction with environmental factors such as diet and lifestyle. Perhaps the confidence of Dr. Collins came from the fact that with the complete human DNA sequence, no polygene can escape. What is more, polygenes can be captured in their tens of thousands by modern microarray DNA chips for simple and efficient testing.However, it is the basic tenet of this editorial that for common conditions such as coronary disease the genetic path leading to DNA diagnostics will be of less utility and benefit than a path that leads to a physiological understanding. The problems are that genetic testing for polygenic conditions will be impossibly complex because of the large number of genes involved and unreliable because of the unpredictability of gene-phenotype associations as well as gene-gene and gene-environment interactions.COMPLEXITY AND FALLIBILITY OF DNA MINUTIAEThe basic goal of DNA testing is to predict disease. This makes sense in a monogenic Mendelian condition in which a mutation absolutely predetermines the outcome. However, even in Mendelian disease, genetic tests are not foolproof. The realities of variable penetrance and phenotypic heterogeneity mean that sometimes a positive genetic test is returned in an unaffected family member (48). If we cannot be assured of reliability of genetic diagnosis for diseases resulting from one gene, why should we expect greater confidence with multiple polygenes?Notwithstanding phenotypic heterogeneity, genetic testing makes sense if the gene has a substantial effect. The more genes that contribute to a condition, the less their individual effects. In the case of coronary disease, the number may be very large (Fig.1). Most of the known coronary risk factors (weight, blood pressure, cholesterol, etc.) are themselves believed to be polygenic. For example, the recent series of genome-wide scans have identified 20 different chromosomal regions that may each encompass a gene or genes that determines blood pressure (17, 21,23, 33, 39, 42, 49, 53). If the same is true for cholesterol and weight, then as many as 60 genetic loci might be relevant. The actual numbers of mutations or variants in these genes might be an order of magnitude higher (Fig. 1). The experience with monogenic disease has revealed allelic heterogeneity with often hundreds of different causative mutations for each implicated gene.Fig. 1.Multifactorial nature of common conditions such as ischemic heart disease involves several risk factors each of which have heterogeneous molecular origins at both the gene and the mutation levels. Interaction between different genes and with the environment (not shown) adds further complexity.Download figureDownload PowerPoint The catalogue of potential coronary genes and variants may indeed fill a microarray chip. This may not present technical problems, but of what use will be the information? Will lots of little bits of genetic information add up to one big useful bit? How confident can we be of each individual marker? The ACE gene story may be repeated many times over. What if (as is likely) there are interactions between the various genotypes such that specific combinations may augment or lessen the additive risks? How will important environmental factors such as smoking be taken into account? What about the ill-defined behavioral and lifestyle characteristics responsible for the decline in the coronary epidemic since the 1950s and 1960s?PRIVATE GENES, PUBLIC HEALTHAt every level, despite precision of the molecular tests per se, genetic complexity works against the development of simple, precise, and reliable diagnostic and prognostic tests for common conditions. Highly technological tests of every conceivable genetic possibility are likely to tell more about one's individuality than the likelihood of coronary disease in later life. Unless we can be assured of genetic tests, we are at risk of creating unnecessary worry or offering false reassurance. Widespread DNA screening for common disease will also raise ethical and privacy concerns.The focus of genetic testing is on the individual, but the fact is that we are all at risk of common conditions such as cardiovascular disease. To a greater or lesser degree we all carry genetic variants that predispose to coronary disease. The enormous power of genetics has the potential to reveal the underlying pathophysiological processes of predisposition and disease that is relevant to us all.PHYSIOLOGICAL CONVERGENCEThen down which path can genetics lead us toward this goal? There is something to be learned from monogenic disease. An illustrative cardiovascular example is hypertrophic cardiomyopathy (HCM). This condition characterized by abnormal cardiomyocytes, hypertrophy, and a propensity to heart failure and sudden death was diagnosed in the pregenetic era by clinical examination and echocardiography alone. Linkage studies in affected families revealed significant genetic and allelic heterogeneity with various mutations in genes encoding the proteins cardiac β-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, α-tropomyosin, and cardiac myosin binding protein (8). Family-specific markers are now useful for preclinical and clinical diagnosis, although somewhat impaired by the occasional occurrence of phenotypic heterogeneity (11).Perhaps the more important implications of the genetic discoveries were those related to function of the genes. There emerged a common thread in that each gene made a protein that was an integral part of the sarcomeric molecular motor of cardiomyocytes. In other words, a diverse range of genetic spanners could be thrown in the works and produce the same clinical picture. Here was a point of convergence at an integrative physiological level that transcended genetic diversity to provide a unifying hypothesis (Fig. 2). In the case of HCM, the race is on to understand and correct the sarcomeric problems (12, 38, 50). The need to identify the missing HCM genes and mutations seems less urgent. Chances are that they will also in some way affect the sarcomere of cardiomyocytes.Fig. 2.From monogenic disease such as familial hypertrophic cardiomyopathy (see text) comes the concept of physiological convergence in which disparate genetic mutations independently cause a common pathophysiological abnormality that leads to disease. In theory it should be possible to triangulate (shaded) the point of physiological convergence from at least 2 independent genes.Download figureDownload PowerPoint Although it has yet to be demonstrated for common polygenic conditions, the concept of physiological convergence is potentially important. In particular, it should be possible to triangulate convergence points (there may be several for each condition) from two or more common genetic starting points (Fig. 2) without having to pursue an exhaustive hunt for every gene and every mutation.PHYSIOLOGICAL SIMPLIFICATION OF GENETIC COMPLEXITYPursuing the path from genetics to physiology has many potential advantages, most prominently that of distilling polygenic complexity to a physiological essence. Faced with the discovery of 20 blood pressure genes, each with 10 functional variants, would it not be more efficient and of greater potential benefit to target the development of novel pharmacological approaches on a point at which their diversities coalesce, rather than trying to counter every known mutation? For those interested in the interaction between the environment and genetic predisposition, the availability of a key physiological manifestation provides a relevant and practicable research focus.It is important to stress that the logical extension of this argument is not that one ignores the genetic basis of disease and simply develops symptomatic treatment for the disease as the final point of convergence. Genetics is needed to discover new mutations of known genes and previously unknown genes that will code proteins contributing to physiological mechanisms of disease.ONWARD AND UPWARDIn the pages of a premier physiological journal this message may be preaching to the converted. More widely though, the center stage of the postgenomic era is held by the first few steps beyond DNA. We are witnessing developments in RNA analyses through expression profiling and proteomic studies through functional and structural genomics. These areas are just as complex as DNA genomic analyses and bioinformatic approaches are being recruited to put these into perspective and order. But it is the leap into the physiological world of living cells and beyond that needs to be given appropriate emphasis.So is genetics leading us the garden path? How could we begrudge a discipline that has brought us the ability to scour the human genome? The problem is not genetics itself, but the simplistic assumption that one's DNA sequence will reliably predict risk of conditions such as ischemic heart disease, cerebrovascular disease, diabetes, and the rest. Even if it were possible, we need genetics to do more than tell us who will succumb to these conditions. We need better ways to prevent disease in people and populations. If through physiological genomics, we can understand how common DNA variants predispose cells, tissues, organs, organisms, and populations to disease processes, then genetics will have done us proud.FOOTNOTESAddress for reprint requests and other correspondence: S. Harrap, Victorian Physiological Genomics Centre, Dept. of Physiology, The Univ. of Melbourne, Victoria, 3010 Australia (E-mail:s.[email protected]unimelb.edu.au).REFERENCES1 Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A.ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites.Arterioscler Thromb Vasc Biol202000484492Crossref | PubMed | ISI | Google Scholar2 Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Sorensen TI, Jensen G, Tybjaerg-Hansen A.ACE gene polymorphism: ischemic heart disease and longevity in 10,150 individuals. 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Origine, fréquence, significationBulletin de l'Académie Nationale de Médecine, Vol. 189, No. 1Angiotensin-converting enzyme gene polymorphism interacts with left ventricular ejection fraction and brain natriuretic peptide levels to predict mortality after myocardial infarctionJournal of the American College of Cardiology, Vol. 41, No. 5Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiolPharmacogenetics, Vol. 12, No. 5 More from this issue > Volume 281Issue 1July 2001Pages H1-H6 Copyright & PermissionsCopyright © 2001 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.2001.281.1.H1PubMed11406461History Published online 1 July 2001 Published in print 1 July 2001 Metrics