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This issue of Heart Views highlights the progress
of genetic research in cardiovascular
disease (Kaneko et.al, p.152 ).
Genes are the focus of one of the most important scientific
activities being carried today. The Human
Genome Project is a vastly ambitious global
effort to identify the 80,000 or so human
genes that exist inside each human cell. The
project officially began in 1990, and
according to early plans, the human race
would witness its own blueprint in fine
detail in the year 2005. However, due to
improvements in technology, the complete DNA
sequence of the human genome will be
available in 2003, two years ahead of
schedule. In March 1999, 15% of the DNA
sequence of the human genome was in a
finished state and it is predicted that 90%
of the human sequence could be completed in
“working draft” form by the spring of 2000.
Scientists predict that when this feat is
accomplished, it should be possible, by
studying a person’s genes, to diagnose
predisposition to many diseases and begin
preventive treatment before a disease can be
manifested. It should be possible to correct
many genetic defects by giving patients new,
properly functioning genes to replace
damaged ones.
Coronary artery disease (CAD) was recognized as a major
public health problem only in this century.
Tremendous advances in knowledge of the
pathophysiology of atherosclerotic
cardiovascular disease led to intensive
efforts at primary and secondary prevention.
These caused a dramatic decline in
cardiovascular mortality by more than 50%
over the last 30 thirty years in the United
States (1). Likewise, spectacular advances
have been made in the management of acute
myocardial infarction and in the long-term
treatment of CAD. Such advances include the
increasing use of beta-blockers, aspirin,
thrombolytic therapy, angiotensin converting
enzyme inhibitors, and lipid-lowering
therapies as well as improvements in
revascularization procedures (2). Clinical
trials of antihypertensive drugs,
lipid-lowering therapies, and smoking
cessation have documented the benefits of
treating these risk factors and established
beyond doubt their causal relation with CAD
(3).
Yet, despite the advances in diagnosis, treatment, prevention, and
the impressive decline in mortality, actual
incidence of the disease has not decreased.
Cardiovascular disease remains the principal
cause of death in men by 45 years of age and
women by 65 years of age in Western
countries (4). In Qatar, cardiovascular
disease is the leading cause of death (5).
Worldwide, the morbidity and mortality from
cardiovascular disease is also increasing.
Between 1999 and 2020, the proportion of
worldwide deaths from cardiovascular disease
is projected to increase from 28.9% to
36.3%, accounting for more than one-third of
deaths throughout the world. Moreover, in
terms of number of years of life lost, it is
projected that cardiovascular disease will
jump in ranking from fourth to first, while
as a cause of premature death and
disability, it will rise from fifth to first
(4). Thus, there is an emerging pandemic of
cardiovascular disease, underscoring the
crucial need to redouble research efforts in
treatment and prevention.
Recent discoveries such as the role of homocysteine, C-reactive
protein and inflammation continue to add
insights to our understanding of the
underlying pathophysiology in
atherosclerosis. It is now clear that the
lesions in atherosclerosis represent an
inflammatory response to various forms of
injury. When the inflammatory response is
excessive, it induces a fibroproliferative,
or healing, response as well. When both
become excessive, they enlarge the wall of
the artery and ultimately impinge upon the
arterial lumen (6).
Numerous factors are involved with the arterial injury that
leads to atherosclerosis. These factors need
to be better understood, and better markers
need to be found to identify individuals at
risk at any age. Atherosclerosis is a
multigenic disease process. Although the
genes and the interactions involved in this
process are not yet fully understood, with
advances in cellular and molecular biology,
new techniques may permit us to determine
which genes are important in the development
and progression of atherosclerotic lesions.
Hopefully, knowledge of specific genes
expressed in each of the principal cells in
the lesions, and determination of their
roles in the various cellular activities
during atherogenesis will permit the
development of specifically targeted
molecules that can be effectively used in
the early diagnosis, treatment, and
prevention of this disease.
Recently, the August 1999 issue of Nature Genetics reported
the discovery of a gene that regulates the
synthesis of HDL-cholesterol. Flaws in the
gene, known as ABC1, prevent the production
of a protein that the body needs to
eliminate excess LDL-cholesterol. The gene
was discovered by researchers looking for
the cause of Tangier disease, an extremely
rare inherited illness characterized by
hypercholesterolemia due to lack of HDL-cholesterol.
Its discovery has created excitement in the
medical community, raising hopes for the
development of a new class of drugs or gene
therapies to boost the body’s HDL-cholesterol.
The problem remains, however, that our
current methods of raising HDL are
inadequate and new methods must be developed
to fully test the hypothesis that raising
HDL will decrease atherosclerotic disease or
cardiovascular events. Furthermore, the
molecular basis of many of the known
inherited lipid disorders has not yet been
discovered. Elucidation of the molecular
mechanisms involved in lipoprotein
metabolism will lead to better methods of
intervening in lipid disorders and to many
more clinical trials designed to test their
benefits in reducing cardiovascular events.
The rules that govern inheritance patterns for many rare
hereditary disorders involving changes in a
single gene follow straightforward Mendelian
rules. But tracking or hunting the genetic
components of complex disorders such as
heart disease, diabetes, and hypertension –
diseases that result from the interplay of
environment, lifestyle, and the effects of
many genes – remains a formidable task. The
direction of genetic research is evolving
from an understanding of single genes and
their individual functions to an
understanding of the actions of multiple
genes and their control of biologic systems.
This requires technical ability to detect
DNA variations(7). Identifying human genetic
variations will eventually allow clinicians
to subclassify diseases and adapt therapies
to the individual patient. Pharmacogenomics,
a rapidly expanding new field, use
information about genetic variation to
predict responses to drug therapies. For
example, the cholesteryl ester transfer
protein (CETP) plays an important part in
the metabolism of HDL, a lipoprotein
associated with lowered susceptibility to
atherosclerosis. A certain genetic variant
of the CETP gene is correlated with higher
plasma CETP levels and lower levels of
plasma HDL. One study showed that in men who
carried this genetic variant, treatment with
pravastatin slowed the progression of
coronary atherosclerosis (8). This finding
may allow physicians to predict which
patients with CAD will benefit from
treatment with pravastatin.
The remarkable advances in molecular medicine have also
generated considerable enthusiasm for
gene-based therapy to reduce
post-angioplasty or stent restenosis,
restore function of the failing heart,
stimulate angiogenesis in refractory angina,
and replace necrotic cells from a myocardial
infarct with functioning myocytes.
Clearly, the application of molecular genetics to human
biology has had a profound effect on our
ability to understand, diagnose, and treat a
variety of diseases. The field of human
molecular genetics is evolving rapidly. The
identification and cloning of a number of
disease-related genes has provided us with a
powerful set of tools for identifying
susceptibility to disease, and more
important, understanding the molecular
pathophysiology of many disorders. Molecular
genetic techniques continue to advance and
information about human genes and the human
genome will increase at a remarkable pace.
Genetic factors that contribute to
cardiovascular disease and modulate human
phenotypes will be defined. This information
will be useful for prediction of risk and
for risk stratification. Biochemical and
physiologic studies of the proteins encoded
by these genes will provide insight into
pathogenic mechanisms and strategies for
therapy.
The end of the 20th century witnessed great progress in genetic
research and the birth of gene therapy. The
major challenge at present is the
development of safe vehicles to achieve
efficient gene delivery. Once this goal is
realized, gene therapy will become a reality
in the 21st century.
Referencess
1. Levy D, Thom TJ. Death rates from
coronary disease progress and a puzzling
paradox. N Engl L Med 998;339:915 – 917.
2. McGovern PG, Pankow JS, Shahar E, et al.
Recent trends in acute coronary heart
disease – mortality, morbidity, medical
care, and risk factors. N Engl J Med
1996;334:884 – 890.
3. Pasternak RC, Grundy SM, Levy D, Thompson
PD. Spectrum of risk factors for coronary
heart disease. J Am Coll Cardiol 1
996;27:978-990.
4. Hennekens CH. Increasing Burden of
cardiovascular disease. Currentknowledge and
future directions for research on risk
factors. Circulation 1998;97:1095 –1102.
5. Mortality of cardiovascular disease in
Qatar. Heart Views, 1999;1:98.
6. Russell R. Mechanisms of Disease:
Atherosclerosis — An Inflammatory Disease. N
Engl J Med 1999;340:115 –126.
7. Wang DG, Fan JB, Siao CJ, et al.
Large-scale identification, mapping and
genotyping of single-nucleotide
polymorphisms in the human genome. Science
1998;280:1077 – 1082.
8. Kuivenhoven JA, Jukema JW, Zwinderman AH,
et al. the role of a common variant of the
cholesteryl ester transfer protein gene in
the progression of coronary atherosclerosis.
N Engl J Med 1998;338:86 – 93.
A Sprinkling of History
From Voyages Of Discovery To Pea Plants To
DNA Helix
In 1859, a revolutionary book was published –
Darwin’s On the Origin of Species, which
proposed his theory of evolution by natural
selection. In Darwin’s view, members of a
population vary in heritable traits.
Variations that improve chances of surviving
and reproducing show up more often in each
generation. Characteristics that do not
improve survival become less frequent. In
time, the population changes – it evolves.
The beginnings of Darwin’s theory of
evolution stemmed from his observations of
plant and animal life during his voyages to
South America, the South Pacific, and
Galapagos islands as the official naturalist
on the research vessel HMS Beagle.
However, Darwin could not explain how various
characteristics were inherited from
generation to generation, to enable species
to change and survive. That piece of the
puzzle came from a scholarly monk named
Gregor Mendel. His theory that those
variants develop within natural populations,
which are then passed on to succeeding
generations, was contradictory to the
prevailing scientific concept of his time.
To test his hypothesis on the patterns of
inheritance, Mendel bred generation after
generation of pea plants. His results were
expressed in simple mathematical ratios, one
of the first biological studies to employ
statistics. He found that certain
characteristics reappeared in fairly precise
ratios; the ones that occurred most often he
called dominant and the others he called
recessive. He believed that these
characteristics were passed on from plant to
plant as “particles”, of which each plant
had two, one from each parent.
Mendel’s findings seem simple enough today. The cells of pea
plants carry two genes for each trait.
Following cell meiosis (two-stage nuclear
division process), the two genes end up in
the male and female gametes. When the two
gametes combine at fertilization, each new
plant again has two genes for each trait.
So, the humble pea plant showed Mendel how
parents transmit discrete units of
information about traits – genes – to
offspring. At that time however, not even
Mendel himself knew that he had discovered
some near-universal rules governing
inheritance. His insights still have the
power to explain many of the puzzling and
sometimes devastating aspects of inheritance
that occupy our attention today.
Although Mendel published an account of his work in
1866, it was mainly ignored. It was only in
1900 that scientists rediscovered and fully
appreciated his work. Since 1869, it was
known that every cell of living tissue
contains a substance called nucleic acid. By
the 1920s, two forms of nucleic acid had
been identified: DNA (deoxyribonucleic acid)
and RNA (ribonucelic acid). After much work
and research, in 1953, the final piece of
the puzzle of inheritance fell into place
when Francis Crick and James Watson
discovered the double helix structure of
DNA.
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