GENETICS IN CARDIOVASCULAR DISEASE
This chapter introduces the clinically important principles of genetics and the application of these principles to clinical medicine. It places an emphasis on the genetics of cardiovascular diseases, the role in pharmacology, and future direction. Genetics mutation epigenetics hypertrophic cardiomyopathy long QT syndrome PCSK9 inhibitor.
FIG 3.1 Epigenetics.
In 1953, Watson and Crick published their landmark paper on the molecular structure of nucleic acids and a
particularly prescient comment was
made: “It has not escaped our notice that the specific pairing we have
postulated immediately suggests a possible copying mechanism for the genetic
material.”
The pace of technological innovation and our resulting understanding of
the relationship of genetics to human disease continues to increase
exponentially. Today, the ability to partially or completely sequence the
genetic code of an individual is an inexpensive commodity, and the current and
future impact of this knowledge continues to increase.
With this knowledge, our understanding of disease associations with the
genetic code has become more complex, beyond simple assessment of various types
of mutations leading to a certain phenotype. This is driven by an
ever-increasing understanding of the interplay between genetic and
environmental factors in disease. Today, in addition to easily understanding
environmental factors important in cardiovascular disease (e.g., smoking, diet,
exercise, and many others), it is apparent that the environment interacts with
the genome in complex ways. Epigenetics, which is the study of changes in gene
modification, or translation-altering gene expression, is now understood to be
a mechanistic explanation, and possibly a therapeutic target for these
environmental–genetic interactions (Fig. 3.1). One classic example of
epigenetics in clinical medicine was the observation of children born to famished
mothers during the Dutch Hunger Winter of 1944 to 1945. These children were
observed in their sixth decade of life and were found to have higher rates of
obesity and coronary artery disease (CAD). Further evaluation showed them to
have decreased methylation of insulin-like growth factor-2, a factor known to
be important in metabolism, energy use, and weight, compared with their
genetically similar siblings. The increased understanding of factors that alter
methylation, histone packaging, and noncoding RNA, to name a few, will lead to
a stronger grasp of the correlation between disease and the genetic code.
Because of the growing complexity and rapid pace of new information presented,
the development of genetic specialists within each field has been paramount to
assist healthcare providers in deciphering this information and its clinical
implications.
The goal of this chapter is to introduce the clinically important principles of genetics and the application of these principles to clinical medicine, with particular emphasis on the genetics of cardiovascular diseases (Table 3.1). A brief glossary of the clinically important terms in this chapter is shown in Box 3.1.
FIG 3.2 Genetic and Environmental Factors in Cardiovascular Disease.
GENETIC EVALUATION: SELECTED EXAMPLES
Cardiomyopathies
In the coming years, it is likely that genetic analysis will play an
increasingly important role in understanding high-risk cardiovascular syndromes. Significant advances have been
made in several cardiovascular phenotypes, as illustrated by the examples in
this chapter.
Hypertrophic Cardiomyopathy
Cardiomyopathy is a term that refers to a heterogeneous group of diseases
that affect the myocardium. Cardiomyopathies result from multiple etiologies,
including ischemia, nonischemic causes (restrictive or infiltrative), and
hypertrophy, each of which has subcategories. The study of familial trends and
transmissible genetic abnormalities in cardiomyopathies has led to more
detailed classification based not only on phenotypic appearance, but also on
genetic alterations. In some cases, this knowledge is of importance for risk
stratification and treatment.
A classic example is hypertrophic cardiomyopathy (HCM), which is defined
as the presence of myocardial hypertrophy caused by myocardial disarray. HCM is
a disease that affects 0.02% to 0.23% of the general population, and in some,
but not all HCM patients, it results in symptomatic diseases due to left
ventricular outflow obstruction and an increased risk for fatal arrhythmias,
such as ventricular tachycardia. Current understanding of the genetic basis of
HCM is complex (Fig. 3.2). Most cases are caused by autosomal dominant
mutations in genes that encode proteins in the sarcomere. Beta-myosin heavy
chain and myosin-binding protein C are the most common genes affected; however,
other genes in the sarcomere protein, including troponins I and T, the
tropomyosin α-1 chain, and myosin light chain-3 have also been implicated in
HCM.
The specific genetic basis for HCM in a given family has allowed a much
better understanding of the disease and its management.
For those with an identifiable genetic cause of HCM, genetic screening of
family members allows for more focused disease surveillance and management at
an early stage before symptoms develop. For those in the same family who lack
the causative mutation, surveillance can be less frequent, or in some cases,
not necessary. The treatment of left ventricular outflow obstruction is not
driven by genetic mutations per se; however, combining pedigree–phenotype
analysis with DNA sequence information can identify those with an increased
risk of sudden cardiac death (SCD) and may be used for decision making in the
use of implantable cardioverter-defibrillator. In addition, genetic testing can
identify a subset of individuals with a positive genotype but a negative
phenotype, which raises new clinical questions, such as whether these
individuals should be excluded from participation of competitive sports, would
benefit from a prophylactic defibrillator, and how often they should be
screened for phenotypic HCM.
Genetic etiologies also underlie numerous autosomal recessive and X-linked metabolic causes of
cardiomyopathy, such as Anderson-Fabry disease, mitochondrial cardiomyopathies,
neuromuscular diseases, and infiltrative diseases. Certain drugs, such as
anabolic steroids and tacrolimus, are also therapies that have been shown to be
causes of HCMs.
Arrhythmogenic diseases result from heterogeneous causes that lead to
atrial and ventricular tachyarrhythmias. Some of these disease processes
overlap with structural heart diseases and cardiomyopathies, such as
arrhythmogenic right ventricular dysplasia and left ventricular non-
compaction, which predispose patients to fatal ventricular tachycardia and
fibrillation. Although molecular causes of these complex phenotypes are only
now being studied, much is known about these disease processes that
phenotypically only affect the conduction system and spare the myocardium.
Long QT syndrome (LQTS) describes a group of diseases whose common
phenotypic feature is an abnormal QT interval on the ECG. Usually patients with
a corrected QT interval exceed the 99th percentile (>450 ms for men and 470
ms for women). QT prolongation is associated with SCD, presumably because of
the propensity for polymorphic ventricular tachycardia (Torsades de pointes)
when a premature ventricular contraction occurs in the refractory period
(prolonged in these cases. More than
200 mutations in 5 different genes (all coding for sodium or potassium channel
proteins or their chaperones) have been reported to cause LQTS (Fig. 3.2; lower
panel). Both autosomal-dominant and autosomal-recessive inheritance have been
described for LQTS, which is the inheritance depending on the gene involved.
Some forms of LQTS manifest only when a secondary cause of QT prolongation is
present, such as electrolyte abnormalities, medications, or myocardial
ischemia. The diagnosis of LQTS can be made by noninvasive (ECG) testing in
most cases (except in the case of LQTS provoked by a secondary cause). For
individuals from families with a history of SCD, careful analysis of the ECG is
necessary, and provocative testing may be indicated in some circumstances.
Nevertheless, the genetic basis for LQTS may be highly informative in terms of
prognosis and as a guide to clinical therapy, as well as for identifying family
members at risk for sudden death. More than 90% of all those with
genotype-positive LQTS have genetic mutations in three main genes: KLNQ1 (its
mutation causing
LQT1), KCNH2 (LQT2), and SCN5A (LQT3). Additional minor
genes, such as KCNE1, KCNE2,
CAV3, SCN4B, SNTA1, ANKB, and KCNJ2, only account for approximately 5% of
genotype-positive LQTS. Com- mercial genetic testing of all these LQTS genes
are available at affordable costs. LQTS is an excellent example of a spectrum
of diseases (which were once clustered together as a single entity) that will
likely benefit from the principles of pharmacogenomics, which is the use of
specific medications based on genotype.
Atherosclerosis is the common pathology underlying a spectrum of arterial diseases, including coronary
heart disease, ischemic stroke, aortic aneurysm,
and peripheral arterial disease. Atherosclerosis continues to be a leading
cause of morbidity and mortality in the Western world and a leading disorder
seen by a broad range of physicians, and in its most extreme form, by
cardiovascular specialists. The heritability of atherosclerotic coronary heart
disease is approximately 50% to 60% with >10 monogenic causal genes and
their mutations reported to cause familial atherosclerotic disease in a
Mendelian pattern with variable penetrations. However, genetic and epigenetic
factors that lead directly or indirectly to the accelerated process of
atherosclerosis are vast and remain incompletely understood.
Recent studies of the genetics of atherosclerosis have made important
advances in the identification of risk alleles for atherosclerosis, yet have also raised important questions about the
usefulness of applying information about the presence of these risk alleles to
clinical decision making. Using unbiased genome-wide association studies of
genetic variants associated with atherosclerotic CAD, several groups
simultaneously identified multiple highly correlated single nucleotide
polymorphisms on chromosome 9 (9p21.3) that identified individuals at increased
risk for developing coronary
atherosclerosis. The immediate cross validation of this risk locus provided a
high degree of certainty that it does incur increased risk of cardiovascular
disease. The merits of screening individuals for these risk alleles are less
certain. More than 50 single nucleotide polymorphisms have been identified to
be associated with an increased risk of atherosclerotic CAD. For individuals
who are known to have clinically significant atherosclerosis,
knowledge of risk allele status is of little value, at least until or if
specific therapies are developed for patients bearing these polymorphisms. For
individuals concerned about their future risk of cardiovascular disease, it is
unclear whether knowledge about risk allele status confers additional
information beyond known clinical risk factors. Attempts to construct a genetic
risk score to provide lifelong prediction of CAD risk, by taking a panel of
genetic variants associated with increased risk of CAD, are at its early stage.
Time and additional research will clarify these issues, but at present the
clinical value of genetic testing for these risk alleles is not established, even if the tests are now easily
available.
