Vol. 281, Issue 1, H1-H6, July 2001
EDITORIAL
Utility of genetic approaches to common cardiovascular
diseases
Stephen B.
Harrap and
Steven
Petrou
Department of Physiology, Victorian Physiological Genomics
Centre, The University of Melbourne, Victoria 3010, Australia
 |
HANDS UP FOR GENETICS |
The 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.
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THE RISE AND FALL OF THE ACE GENE |
A 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 landmark Nature 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 ACE
D 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 the
D 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?
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FROM GENES TO THE GENOMES |
As 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?
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THE CHALLENGE OF COMMON DISEASES |
One 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.
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COMPLEXITY AND FALLIBILITY OF DNA MINUTIAE |
The 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.
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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.
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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?
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PRIVATE GENES, PUBLIC HEALTH |
At 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.
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PHYSIOLOGICAL CONVERGENCE |
Then 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 
-myosin heavy chain, ventricular myosin essential
light chain, ventricular myosin regulatory light chain, cardiac
troponin T, cardiac troponin I, 
-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.
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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.
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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.
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PHYSIOLOGICAL SIMPLIFICATION OF GENETIC COMPLEXITY |
Pursuing 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.
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ONWARD AND UPWARD |
In 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.
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FOOTNOTES |
Address 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.harrap{at}physiology.unimelb.edu.au).
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Am J Physiol Heart Circ Physiol 281(1):H1-H6
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