As the leading cause of death in the United States is cardiovascular disease
(CVD), with over 700,000 deaths attributable annually to the diseases of the
heart and nearly 170,000 more resulting from cerebrovascular diseases in 2000,
we should take a look at the role of inheritance. We know that lifestyle is
important and that the risk factors include high blood pressure, diabetes,
smoking, high blood cholesterol and advanced age. We can alter our lifestyles to
reduce the risk, but molecular scientists have already found many genetic
contributions to the disease. Family history which includes the interaction
among enviromental, genetic and behavioral elements, provides a reliable means
of assessing CVD.
Persons who discover they’re in the high-risk category usually respond to
this threat by adopting CVD risk-reducing behavior. (Ref. Table 1)
Because CVD involves so many physiological functions and varieties of
tissue (e.g., muscle fibers, elastic tissue, endothelial linings of arteries,
fat, blood platelets, etc.), the investigations are taking place on many
Strategies for Treatment
The best strategy for dealing with genetic heart disease is to identify those
who are at risk as early as possible and begin treatment which can minimize the
effects of the inherited traits. It has been found that the correction of
lipoprotein disorders is effective in slowing down the clinical progression of
the disease in some patients, especially the reduction of low density
cholesterol. But 80 percent of individuals who develop heart disease have normal
cholesterol levels, so it’s apparent that the treatment has to be somewhat more
specific. Although so far most of the educational efforts have stressed the
reduction of low density cholesterol (LDL) in the blood, there are many other
lipoprotein disorders involved and overcoming these metabolic traits could save
very many lives as well as billions of dollars now spent on the prevention and
treatment of early onset heart disease.
Numerous studies are disclosing that many genes can play roles in this
disease. Here are just some currently under investigation (not necessarily in
the order of importance):ACE, ADH-3, ApoA1, ApoE, apo(a), beta-ENaC and
gamma-ENaC, CETP, Gly46OTrp, HPA-2 Met, VNTR B, ITGB3, LDLR, PTGIS, UCP-3.
Please excuse us if we’ve overlooked your favorite gene, but over 250 different
ones have implicated in coronary artery disease. These genes have vastly
different functions and some of them have multiple variants. There are also
other genes associated with hypertension. High blood pressure afflicts about 25
percent of adults world-wide and is a major risk factor for fatal heart
An example of ongoing genetic research on heart disease are studies of a
lipoprotein, Lp(a) that resembles the low density cholestrol (LDL) which doctors
dread. It has an attached abnormal protein. Plasma levels are genetically
determined by a chromosome 6 locus and it’s inherited in a mendelian dominant
fashion, so about half of the children whose parents have high Lp(a) levels will
develop a similar condition. Its presence has been shown to be a risk factor for
heart attacks and for clotting combinations.
Better Than Cholesterol Testing?
High levels of apolipoprotein B (apoB) and low levels of apolipoprotein A-1
(apoA-1) have been found to be predictive of fatal myocardial infarction (MI),
regardless of serum cholesterol levels. Dr. Goran Walldius and his associates in
Sweden collected data on over 175,000 men and women and found that apoB
concentrations and the apoB/APOA-1 ratio positively correlated with increased
risk of fatal MI. These tests may eventually supplant cholesterol studies for
assessment of MI risk, but the assay methods and quality assurance values need
improvements before the tests can be used routinely.
Genetic Aspects of High Blood Pressure
Hypertension, or high blood pressure, affects around 25 percent of adults
world-wide and is a major risk factor for fatal heart attacks, along with
stroke, kidney failure and heart failure from congestive heart disease. It
affects over 50 million Americans. A research group led by Richard Lifto
identified two genes which cause a kidney disorder and lead to hypertension.
These genes, WNK1 and WNK4, have mutations adversely affecting mechanisms
regulating blood pressure, and the researchers hope that it will be possible to
develop new specific medications which could provide another way to reduce fatal
heart disease. Hypertension research is obviously complex because there are so
Other scientists from the University of Cambridge and Incyte, studying the
molecular basis of type 2 diabetes, used SNP technology which they reported as
confirming a key gene responsible for this type of diabetes, severe insulin
resistance and early onset hypertension. The research is an example of what
Incyte refers to as the “candidate gene approach” to identify novel disease
pathways and drug targets, using biology and bioinformatics combined with
proprietary and public gene sequences to identify genes which would be potential
targets for specific drugs. Detection of polymorphic genes plus genotyping
technologies help establish the relationship between diseases and potential
Another investigative avenue is followed at Wake Forest University, where
they are investigating the regulation of genes involved in vascular disease.
They are also studying various mechanisms, such as enzymes, which the human body
has developed to repair DNA damage at the cellular level.
Research is also under way to see if any anti-hypertensive therapy can be
tailored to specific genetic variations. A protein called “adducin” which
is found on the inner surface of cell membranes, has a genetic variant known to
increase the retention of sodium by the kidneys. Investigators feel that
indentifying this variant would help recognize patients who could be treated
effectively with diuretics, greatly decreasing their chances of experiencing a
stroke or MI.
Early Death from Cardiovascular Disease
Is your heart too big? Did one or more of your relatives die at an early age
from CVD or stroke? If so, there are some conditions besides hypertension which
could have caused this early demise. One of them is cardiomyopathy. Being
a big-hearted person is usually considered a compliment but its implications for
a long, healthy existence can be quite dire, enough to make you heavy-hearted
instead. What physicians call “hypertropic cardiomyopathy”
(HCM) is actually the dilatation of one or both ventricles, the two large
chambers which pump blood out of your heart, accompanied by impaired contraction
of the walls during the pumping process. This often causes heart failure, with a
high rate of sudden death, and can be a major reason to consider heart
Hypertrophy of the heart’s left ventricular wall, which pumps bood throughout
most of your body, greatly affects morbidity and the mortality from such
conditions as MI, congestive heart failure and stroke. It occurs in 16 percent
of whites, 33 to 43 percent of African-Americans and from 22 to 60 percent of
people with hypertension. In Britain the incidence is reported as 1/500.
Heritability of HCM is 26 percent in whites and 70 percent in African-Americans.
Several chromosomal loci are currently under study and may help us to understand
the genetics.The genetic factors aren’t yet well understood, but some
studies at the University of Ottawa involve a protein thought to take part in
energy expenditure and may possibly be involved in the effects weight loss have
on obese women when they take energy-restricted diets. At McGill, studies of ACE
genotypes in sporadic HCM found no differences from the general population, but
there may be genetic abnormalities not yet recognized. B. D. Lowes and
associates at the University of Colorado have found other genetic influences in
patients with HCM; these affect contractility and enlargement of cardiac muscle.
This is just a glimpse of busy research projects spanning the globe.
Sticky Platelets Found at Fault
Two genetic abnormalities increasing the risk of early onset cardiac death
have been found by Dr. J. Mikklesson in Finland. These variants, which were
demonstrated in 20 percent of white males in his series of 700 autopsies,
occured in 60 percent of people who were under the age of 55 when they died
suddenly of cardiac causes. Deaths were attributed to increased platelet
adhesion which had resulted in old organized blood clots in the coronary
arteries. Organized blood clots, or thrombi, are gradually penetrated by
multiple tiny blood vessels coming from the underlying muscular walls of the
blood vessels. Instead of being dissolved, they become permanent obstructions
which can even become calcified, narrowing or completely blocking the lumens of
the vessels which nourish the muscular walls of the heart.
A third condition to consider as a possible cause of your relative’s death at
an early age is a rare, but deadly disease known as
homocysteinemia.Children who have this disease develop lesions of
the heart and brain at an early age. They can have a stroke as early as age 20
years and 18 percent die by the age of 30. Adults with elevated homocystein
levels also have a high risk of stroke.
The Role of Infection
The importance of infectious agents in myocardial infarctions has been
recognized for some time and is now under more intense investigation, including
evaluation of the prophylactic use of certain antibiotics either to prevent MI
or lessen the inflammatory reaction. So far there has been no conclusive
evidence that antibiotics are useful in preventing MI but no doubt there are
other studies yet to be reported. It also raises the possibility that one day it
might be feasible to vaccinate persons at risk.
All in a Heartbeat -- Just Too Fast
Back in 1930, three doctors named Wolff, Parkinson and White described a
peculiar phenomenon in which the hearts of apparently healthy young people
suddenly would begin to pound rapidly, or as they put it, were prone to
paroxysmal tachycardia. For some unknown reason, it was especially common
in China, but the Wolff-Parkinson-White syndrome also affects up to 3/1,000
persons in Western countries and can cause sudden death. It was found to be
heritable as an autosomal dominant disorder, so there is strong familial
involvement. A gene responsible for this syndrome was described in 2001 by
Gollob and numerous other investigators. (The ratio of affected family members
to the investigators was only about 3:1, which gives some idea of the intensity
of the study.) The cause of the condition was found to be a “missense mutation”
on this gene.
Blame It on Mom!
As we learn more about mitocondrial DNA (mtDNA), we find that its proper
function is essential for normal cellular metabolism. As you recll, it’s passed
down unmodified from a mother to all her offspring and very much involved with
energy production. Mutations of mtDNA are already catalogued and linked to
degenerative diseases; they often involve entire systems rather than discrete
organs and especially affect those organs which require a lot of energy. Some
mitochondrial defects are acquired, rather than inherited.
Defects from mtDNA may appear at birth or may not be apparent until middle
age. The ones affecting heart muscle can block the cardiac conduction which
controls heartbeat and cause sudden death. Government grants are now available
to study the role of mtDNA in such conditions as ischemic heart disease (lack of
proper nourishment and oxygen supply to the heart walls), idopathic dilated
cardiomyopathy (the heavy-hearted patients) and various heart conditions
associated with aging.
A Drink a Day, If your Genes Say “O.K.”
There are some epidemiological studies and innumerable self-serving
interpretations of these studies reporting a reduced risk of MI associated with
a moderate consumption of alcohol. The mechanisms for this symbiotic
relationship are still under debate and could also include environmental
factors, such as lifestyle, or variables in the alcoholic beverages, such as red
vs. white wine.
A polymorphism in the gene for alcohol dehydrogenase type 3 (ADH3) is known
to alter your rate of alcohol metabolism. Lisa M. Hines and a jolly group of
researchers studied the relationships among this ADH3 polymorphism, the level of
alcohol consumption and the risk of MI in 396 patients in whom MI had been
recently diagnosed. These were compared with almost twice that number of
strictly sober controls. Records were also kept of the patients’ and the
controls’ HDL levels. Subjects homozygous of an allele associated with a slow
rate of ethyl alcohol oxidation, compared with those with the allele associated
with a fast rate, showed a lower risk of MI. Moderate alcohol consumption was
associated with a decreased risk of MI in 3 genotype groups if the participants
consumed at least one drink per day. As compared with the control subjects,
patients who’d experienced a MI had a higher prevalence of diabetes, angina and
hypertension and were more likely to have a parent who’d had MI before age 60.
The patients consumed less alcohol, took part less often in vigorous exercise,
had higher cholesterol and lower HDL levels.
The conclusions were that moderate drinkers (loosely defined as one drink per
day) homozygous for the ADH3 allele have a substantially decreased risk of MI.
Men who consumed this quantity and were homozygous for the slow-oxidizing
allele, had the greatest reduction in risk. In case you are wondering, they did
NOT extrapolate these results to suggest that two or more drinks per day further
reduced the risks for MI, perhaps leaving this research for a later date. They
did remark that heavy consumption of alcohol puts one at risk for alcoholism,
stroke and liver disease.
Genetic Testing for CVD?
As in many other diseases, gentic testing isn’t usually performed in CVD.
Clinicians are more interested in evaluating cardiac risk and the results of
their treatment in acute cases. Numerous modifications to life style, as shown
in Table 1, have proved helpful. If you know you have familial
hypercholesterolemia, you can contact registries which offer other supportive
Meanwhile, important genetic research continues on the leading causes of CVD
in the developed world. Each new finding brings a little better understanding of
the problem and possible new opportunities to diagnose, treat or monitor heart
disease. As we learn more about the numerous genetic aberrations which accompany
some heart disease, it will enable physicians to personalize treatment and
tailor medications so the most effective ones are administered in the most
efficient manner. We previously mentioned indications that ethnic groups are
responding differently to the medications in current use. Knowing you are
descended from ethnic group in which a particular beta-blocker isn’t effective
could be a highly valuable by-product of your genomic/genealogy research,
especially as alternative beta-blockers have now been
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