Common diseases are currently defined by their clinical
appearance, with little reference to mechanism. Molecular
genetics may provide the tools necessary to define
diseases by their mechanisms. This is likely to have pro
found effects on clinical decisions such as choice of
treatment and on our ability to characterise more clearly
the course of disease and contributory environmental
factors. This information also raises the possibility that
new therapeutic interventions can be obtained rationally,
based on a clear understanding of pathogenesis. Most of
these genetic factors will act as "risk factors" and should
be managed ethically and practically, as would other risk
factors (in hypertension or hypercholesterolaemia, for
example). The rapid advances in human molecular genetics
seen over the past five years indicate that within the next
decade genetic testing will be used widely for predictive
testing in healthy people and for diagnosis and
management of patients.
Molecular genetics was originally used in medicine to
map and identify the major single gene disorders, such as
cystic fibrosis[1] and polycystic kidney disease.[2] The
excitement in the field has shifted to the elucidation of the
genetic basis of the common diseases. With the help of
very large, well characterised family collections, genetic
linkages for many of the major causes of morbidity and
mortality in Western populations have been identified.
The genes and DNA variants responsible for these
disorders are now being cloned at an ever increasing pace.
Large scale genotyping, increasingly integrated genetic and
expressed sequence maps,[3] and large scale sequencing
programmes[4] have all contributed to this remarkable
evolution in our understanding of how genes might modify
our susceptibility to disease.
Considering the current rapid acquisition of genetic
information relating to common disease and the dramatic
technological developments that continue to fuel the field,
it would be surprising if most of the major genetic factors
involved in human disease were not defined over the next
5-10 years. This information will form an important
template for redefining disease, clarifying biological
mechanisms responsible for disease, and developing new
treatment for most disorders.
The rapid developments in human molecular genetics
have often been underestimated, largely due to a failure to
recognise the power of new technologies being applied to
the problem. The use of information encoded within the
genome for clinical practice has previously been limited by
problems of scaling up accurate detection of DNA
variation for rapid and inexpensive analysis. The problem
will soon be resolved, perhaps by the use of
oligonucleotide array technology or "chips."[5] The ease
with which this can be accomplished will determine how
widespread DNA diagnostics will become, but there is
little doubt that the problem is likely to be solved,
technologically, in the near future.
The role of genes for susceptibility to disease has
been emphasised in clinical medicine; it is now clear
that this represents too narrow a perspective for the
genetics of the future. Although such genes will be critical
for redefining diseases and understanding their
pathogenesis, equally important will be loci that determine
disease progression, disease complications, and response
to treatment.
A new taxonomy of disease
Perhaps the most important single contribution of the new
genetics to health care is that it will create a biological
rather than a phenotypic framework with which to
categorise diseases. Clinical physiology and biochemistry
have provided many insights into the biological
disturbances that accompany disease, but it is genetics
that is able to identify the pathways that are
unambiguously involved in pathogenesis. Such genetic
information will eventually lead to the redefinition of
disease on the basis of biochemical events rather than
phenotype; on molecular events driving biological
processes rather than a correlation of clinical syndromes
and outcomes.
The ability to redefine common human disease, using
genetics to define the biochemical processes responsible
for disease, will allow the subdivision of heterogeneous
diseases such as hypertension or diabetes into discrete
entities. Such subdivision is likely to help explain the wide
variation of these diseases, including apparent differences
in physiology, clinical course, and response to treatment,
and it might also provide a basis for identifying
environmental factors that contribute only to certain
subtypes of disease. This has already begun in diabetes,
where definition of the involvement of HLA genes
suggested an immune mechanism in a subset of patients,
leading to the subdivision into type I and type II diabetes.[6]
More recently, type II diabetes has been subdivided
further on the basis of distinct mechanisms involving
glucose phosphorylation and insulin (glucokinase)
secretion, transcriptional regulation (HNF), and insulin receptor
dysfunction.
Disease mechanisms have led to clear definitions of
infectious diseases. For example, our understanding of
hepatitis has progressed: it used to be viewed as a clinical
syndrome with a wide variety of outcomes, and is now
seen as a set of quite specific diseases defined by the
aetiological agent, each with its own clinical course,
prognosis, and (perhaps) response to treatment. An
understanding of the biological process underlying the
clinical phenotype has been of unquestionable benefit in
defining and managing disease, and doctors are unlikely to
attempt to manage a jaundiced patient with
hepatitis without attempting to define the specific viral
agent involved. Similarly, pharmaceutical companies are
unlikely to attempt to develop novel vaccines or therapies
without precise information about the disease type. Even
in a well defined disease such as viral hepatitis, aspects of
disease progression such as viral persistence will need to
await genetic clarification.
Understanding the biological events and pathways
identified by genetics as contributing to disease
lead to clear definition of disease. Such information may
become the starting point in the management of most
patients.
A new taxonomy of disease based on genetics is
already being developed. The first examples of disease
definition have come from the loci in common disease
that seem to resemble autosomally inherited traits in
families. Although these contribute to disease in only a
small proportion of affected people, they provide
consider-able insights into disease mechanisms. Breast
cancer (BRCA1, BRCA2),[7 8] colon cancer (FAP,
HNPCC),[9] and diabetes (MODY 1, 2 and 3)[10-12] all have
such highly penetrant loci, and their elucidation has
provided some of the first insights into disease
pathogenesis. The controversy over the potential role of
impaired insulin secretion versus insulin resistance has
been clarified by our understanding of mechanisms that
result in each type of pathophysiology (glucokinase
mutations versus insulin receptor mutations). Disease
genes that contribute a component of susceptibility but
require other genetic and environmental factors for disease
to occur are also now available for disease definition. Apo
E4 involvement in Alzheimer's disease is leading to
revelations about its pathogenesis,[13] while angiotensin
converting enzyme[14] and angiotensinogen[15] probably
contribute to different forms of cardiovascular disease in
more predictable ways. The result of these developments
is that we are beginning to move toward a refined
taxonomy in medicine that is based on biochemical
mechanisms and driven by genetics.
Genetic information in clinical practice
Early diagnosis, patient stratification, and improved management
With an increasing trend to focus healthcare resources so
that they are most efficiently used, to develop accurate
definition of disease to predict its clinical course, to target
other forms of screening, and to choose optimal treatment,
it is likely that genetic information win be an essential
part of future clinical practice. Already it is possible to
identify people at high risk of breast or colon cancer and to
focus screening (such as mammography or colonoscopy)
or early interventional treatment on these groups. In both
breast and colon cancer we understand the genetic basis for
about 5% of cases, a sufficiently large number of patients
to overwhelm the already stretched genetic screening
capacity in the United Kingdom. As we learn more about
the effect of individual mutations on phenotype and as we
identify more high frequency, low penetrance genes in
both of these diseases, the pressure for screening in
populations with and without symptoms will increase.
Similarly, in diabetes, both the aetiological mutations
(HNF, glucokinase)[10 11] and other loci (ACE)[16] contribute to
the course of the disease or the frequency of
complications; hence these and other genes will be
important prognostic indicators for those managing the
disease and will need to be tested for. Even relatively
simple management decisions regarding individuals at risk
of deep venous thrombosis (patients with total hip
replacement, or those taking the oral contraceptive pill)
may benefit from evaluation of their factor V Leiden
status.[17] Decisions about the best treatment (CETP alleles
and statins, 5'-lipooxygenase in asthma, or tacrine in
Alzheimer's disease) or the side effects of drugs
(cytochrome P-450 and flecanide) may rely on genetic
stratification.[18] These and many other indications for the
use of genetic screening in patients with disease are likely
to emerge in the coming years, and the pressure from
patients and doctors for such services is likely to increase
steadily.
Discovery and development of drugs
One of the earliest applications of this genetic information
will be in the discovery and development of new drugs.
Genetics is now widely used to identify new targets for
drug designs, and it is increasingly recognised that defining
disease populations by genotype will probably correlate
with response to drug treatment The variety of
mechanisms that underlie complex disease may account for
the wide variations in response seen in clinical practice
and the difficulty often encountered in
drug development of showing consistent large benefits in
trial populations. Wise pharmaceutical companies are
already introducing genotyping in their trials to predict
response, and eventually this information will be needed to
protect individuals from receiving a drug if they are
unlikely to respond to it. Effort will also be focused on
defining more clearly the basis for severe side effects of
drugs and not giving them to people likely to experience
side effects. Disease definition and drug response will go
hand in hand, and lifelong treatment is unlikely unless an
accurate genetic diagnosis provides an indication of
response. Development of drugs along genetic guidelines
will be a major force driving implementation of genetic
screening by healthcare providers, as both response to
treatment and complications will have been defined
genetically for many new therapeutic agents.
Genes as risk factors
An indication of how important genetic information will
be in defining disease and predicting outcomes in complex
diseases can be gained from our knowledge of Apo E4 and
Alzheimer's disease. Homozygosity for this allele is
associated with a shift of about 20 years in the average age
of onset of Alzheimer's disease.[13] These effects are at least
as great as other more conventional risk factors in common
disease (such as hypertension in hypercholesterolaemia).
Although Current recommendations suggest that Apo E
genotyping be used as an adjunct to diagnosis in
cognitively impaired people, it is likely that genetic
stratification by Apo E genotype will define drug
response, and hence such genotyping may soon be applied
in clinical trials and eventually will be more relevant to
daily clinical practice.
Examples such as Apo E4 raise the question of
whether a genetic susceptibility factor might best be
treated as another "risk factor." Other risk factors (blood
pressure or cholesterol concentrations) show similar
patterns of incomplete penetrance and have been
considered for population screening. There is little reason
that risk factors based on DNA should not be treated in
the same way. Genetic factors that can be used to predict
the risk of a population rather than an individual should be
viewed in the same way as other risk factors, particularly
if safe treatment or environmental modification were
available.
This raises the possibility of population screening to
detect important susceptibility loci when intervention
becomes available. The obvious requirement for such
screening would be validation by large scale trials
on the benefits of such early detection and treatment A
combination of conventional and genetic risk factors may
be optimal for identifying populations at risk. In
hypertension or hypercholesterolaemia, risks vary greatly.
Treating the extremes of variation has the most favourable
cost benefit ratio, but most "at risk" patients fall within
the normal range. Genetics could be used to identify those
who have additional genetic risks and in whom reduction
of these variables might be beneficial, even where such
variables might be in the "normal" range. There are some
trial data to support such an
approach.[19]
Conclusion
The widespread redefinition of disease through genetics
will be accompanied by the use of genetics for prediction
and diagnosis and to optimise treatment in most common
diseases. This is likely to occur within the next decade.
Testing for genetic "risk factors," even in people without
symptoms, may develop (as it has for other risk factors),
and this information may he used to identify people at
increased risk, for early intervention. There is a
possibility, however, that DNA diagnostics and
pharmacogenomics will be used without proper
evaluation--especially as few resources are available for rigorous
evaluation and pressure continues to introduce this
information in routine clinical practice.
Funding: Wellcome Fund.
Conflict of interest: JB sits as a non-executive member on the
board of Oxagen, a genomic biotechnology company, but holds no equity.
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Identification of the cystic fibrosis gene: cloning and characterisation of
complementary DNA. Science 1989;245:1066-73.
[2] European Polycystic Kidney Disease Consortium. The polycystic kidney
disease 1 gene encodes a 14 kb transcript and lies within a duplicated
region on chromosome 16. Cell 1994;77:881-6.
[3] Schuler GD, Boguski MS, Stewart EA, Stein LD, Gyapay G, Rice K, et al. A
gene map of the human genome. Science 1996;274:540-6.
[4] Marshall E. Genome researchers take the pledge. Science 1996;272:477-8.
[5] To affinity ... and beyond [editorial]. Nature Genet 1996;14:367-70.
[6] Ludworth AG, Woodrow JC. HL-A antigens and diabetes mellitus. Lancet
1974;2:1153.
[7] Miki Y, Swensen J, Shattuck-Eidens D, Fureal PA, Harshman K, Tavtigian S,
et al. A strong candidate for the breast and ovarian cancer susceptibility gene
BRACT. Science 1994;266:66-71.
[8] Wooster R, Bignell G, Lancester J, Swift S, Seal S, Mangion J, et al.
Identification of the breast cancer susceptibility gene BRCA2. Nature
1995;378:789-92.
[9] Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell
1996;87:159-70.
[10] Yamagata K, Hiroto F, Oda N, Kaisaka PJ, Menzel S, Cos NJ, et al.
Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes
of the young (MODY1). Nature 1996;384:458-60.
[11] Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al.
Familial hyperglycemia due to mutations in glycokinase: definition of a subtype
of diabetes mellitus. N Engl J Med 1993;328:697-702.
[12] Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, et al.
Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset
diabetes of the young (MODY3). Nature 1996;384:455-8.
[13] Roses A. Apolipoprotein E genotyping in the differential diagnosis, not
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[14] Cambien F, Porier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al.
Deletion polymorphism in the gene for angiotensin-converting enzyme is a
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[15] Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru
A, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell
1992;71:169-80.
[16] Schmidt S, Schone N, Ritz E. Association of ACE gene polymorphism and
diabetic nephropathy? The Diabetic Nephropathy Study Group. Kidney but
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[17] Ridker PM, Miletick JP, Stampfer MJ, Goldhaber SZ, Linkpainter K,
Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous
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[18] Nebert DW. Polymorphisms in drug-metabolising enzymes: what is their
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Related Article: Summary points
Genetic information is likely to transform the
practice of clinical medicine
Genetics will provide a taxonomy of disease that is
based on biochemical mechanisms rather than
phenotype
Genetic information will be used to identify
individuals who are likely to respond to or suffer
toxicity from drugs
Genetic variation will be another form of "risk
factor" and will permit early treatment and
directed screening
RELATED ARTICLE: A new taxonomy of disease: diabetes
Type I
Autoimmune (HLA,INS)
Type II
Insulin resistant (INS receptor)
Insulin secretion (glucokinase)
Insulin transcription (?) (HNF1[Alpha], HNF4[Alpha], IPF)
Relate Article: Clinical benefit accruing from genetic studies of disease
* A new taxonomy of disease based on mechanisms,
not phenotype
* New drugs developed rationally from our
understanding of pathogenesis
* Drug development and
utilisation focused on disease subtypes likely to respond
to treatment
* Adverse effects of drugs avoided by
genetic screening
* "Risk factor" analysis will facilitate
environmental modification, screening, and
therapeutic management of people before they
develop symptoms
This is the first
of four articles
discussing the
broader
implications of
advances in
genetics
Nuffield Department
of Clinical Medicine,
University of Oxford,
John Radcliffe
Hospital, Oxford OX3 9DU
John Bell, Nuffield
professor of clinical
medicine
john.bell@ndm.ox.
ac.uk
BMJ 1998;316:618-20
COPYRIGHT 1998 British Medical Association
COPYRIGHT 2000 Gale Group
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