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Current Concepts of Cerebrovascular Disease and Stroke
Genetic Aspects of Cerebrovascular Disease
Mark J. Alberts, MD
I
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n the past conventional wisdom held that stroke
and other forms of cardiovascular disease were
due primarily to environmental factors and that
genetic background played a relatively minor role in
disease pathogenesis. However, recent discoveries in
the fields of molecular and population genetics have
suggested the need to reexamine the role of genetic
factors in the pathogenesis of vascular disease.
Research into the genetics of stroke presents some
unique challenges since stroke is a heterogeneous
disease with multiple risk factors. However, such
studies provide an opportunity to elucidate the etiology of stroke at a molecular level and to attempt true
primary prevention. This article reviews some of the
principles of inherited disorders and genetic research
techniques and applies the concepts to the study of
the genetics of specific stroke types.
Over 3,000 genetic disorders have been described in
man, but the gene defect responsible for a specific
disease has been identified for only a handful of
diseases. Many genetic diseases are termed "simple"
diseases: they follow a clear Mendelian pattern of
inheritance (e.g., autosomal dominant, X-luiked recessive) and are due to a defect in only a single gene, and
every individual with the gene defect will display the
mutant phenotype. Examples of simple neurogenetic
diseases include Huntingdon's chorea, Duchenne's
muscular dystrophy, and myotonic muscular dystrophy.
The "complex" genetic disorders are thought to be
due to multiple gene interactions (perhaps influenced by environmental factors), with variable clinical expression of the disease phenotype.1 Examples
include diabetes, cancer, and atherosclerosis. The
study of complex genetic disorders is complicated by
numerous factors:
1) Environmental factors: Extrinsic influences such
as diet, smoking, and stress may be responsible for the
modified expression of certain genetic traits. For example, an individual with the genetic propensity for
hyperlipidemia may reduce serum cholesterol by eating a modified diet. Likewise, genetic factors may have
a role in determining how much an individual eats,
how one handles stress, and who chooses to smoke.
2) Risk factors: It is apparent that the development
of certain major risk factors such as hypertension and
diabetes are under some genetic influence. It is likely
that these risk factors are themselves synthetic traits
(see below) and are also partially influenced by
environmental factors.
3) Synthetic traits: Multiple genes can interact to
produce a trait. Atherosclerosis or hypertension may
be examples of synthetic traits. Since complex genetic
diseases may be due to several synthetic traits acting
together, analysis of such interactions becomes exceedingly complex.
4) Polygenic trait: In this case abnormalities of
multiple genes are necessary to produce a specific trait.
5) Genetic heterogeneity: Defects at more than
one genetic allele can produce similar phenotypic
abnormalities.
6) Phenocopy: An environmental factor can produce a mutant phenotype identical to that caused by
a defective gene. For example, a dissection of the
carotid artery due to neck trauma can produce a
stroke with clinical findings similar to atherosclerotic
occlusion of the carotid artery.
Two genetic terms which are often misunderstood
are penetrance and expressivity. Penetrance is an
all-or-nothing phenomenon: a genetic disease is completely penetrant if every person carrying the mutant
genotype expresses the mutant phenotype and incompletely penetrant if some individuals carrying the
mutant genotype do not have the mutant phenotype.
Variable expressivity refers to the propensity of some
genetic disorders to produce quite varied phenotypic
findings. Neuroflbromatosis is an example of a genetic disorder with variable expressivity.
The issues described above are important for understanding genetic diseases in populations. The
techniques described below are used for studying the
molecular genetic abnormalities responsible for
these complex diseases.
From the Stroke Acute Care Unit, Division of Neurology,
Department of Medicine, Duke University Medical Center,
Durham, N.C.
This work was supported in part by grants T-32-NS07274 and
P-50-NS06233 from the National Institutes of Health, Bethesda,
Md. Dr. Alberts is a recipient of a National Institutes of Health
Fellowship Training Award in Cerebrovascular Disease.
Reprinted from Current Concepts of Cerebrovascular Disease and
Stroke 1990;25:25-30.
Molecular Genetic Techniques
The goal of molecular genetic research is to identify and characterize the genetic defect responsible
for a specific genetic disease. The magnitude of this
task can be better understood when it is realized that
the human genome has over 3 billion bases of DNA
organized into about 100,000 genes. Since only a
small number of specific genes have been isolated
Alberts Genetic Aspects of Cerebrovascular Disease
and characterized, the genes responsible for most
genetic diseases have not been identified.
Classic genetic research has attempted first to find
the defective protein and then to isolate the abnormal gene. However, since the abnormal protein responsible for most genetic diseases has not been
found, a new approach is warranted. This approach,
termed reverse genetics, uses genetic linkage analysis
to identify chromosomal regions that are close to
disease loci. One advantage of reverse genetics is that
no a priori information about the location of the
mutant gene is necessary. Linkage can be tested with
probes (fragments of DNA) that are scattered
throughout the human genome. The specific techniques and terminology of reverse genetics have been
reviewed recently, and the interested reader is referred to these excellent references for more detailed
information.1'2
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One of the key steps in studying genetic linkage is
to identify sufficiently large families with the disease
of interest. If the familial form of the disease is rare
or the available families do not have multiple generations or many living members available for testing,
the usefulness of classic genetic linkage studies becomes somewhat limited. Because of the likely multigenic pathogenesis of stroke, classic genetic linkage
analysis may be insufficient to find linkage.
Some of these problems may be overcome by using
newer methods of linkage analysis. The affected
pedigree member (APM) method, developed by
Weeks and Lange,3 uses marker phenotypes for
APMs only. This technique is more sensitive for
distantly related relatives that are affected and share
the same rare allele. Another advantage of the APM
method is that no assumptions about the mode of
inheritance are required.
Another potentially powerful technique is the affected relative pairs (ARP) technique.4 Various combinations of pairs of affected relatives (siblings, first
cousins, half sibs, etc.) can be used to identify major
or minor disease susceptibility loci. This approach is
attractive in cases where large immediate families
may not be available but members of extended
pedigrees are still alive. Both the APM and ARP
methods may be most useful for identifying major
gene effects in the pathogenesis of complex diseases
rather than identifying every gene involved in an
inherited disease.
Stroke Genetics
Risk Factors
The well-documented risk factors described for
stroke include hypertension, diabetes, lipid abnormalities, heart disease, advanced age, fibrinogen levels, smoking, and coagulation defects. Many of these
risk factors are probably synthetic traits themselves
(e.g., hypertension, lipid levels) while others have a
stronger environmental component (i.e., smoking). A
recent study evaluated the relative importance of
genetic and environmental factors in determining
277
blood pressure, lipid levels, and body mass index in
over 300 twins and 1102 healthy adults. This study
found that genetic background had a significantly
greater influence on these risk factors than environmental components.5
Another risk factor that is receiving increasing
attention is fibrinogen. Several studies have shown a
correlation between plasma levels of fibrinogen,
stroke risk, and the rate of progression of carotid
atherosclerosis.6'7 The control of plasma fibrinogen
levels may be under both environmental and genetic
control. Since fibrinogen is an acute phase reactant, it
increases as a result of various injuries (including
stroke or myocardial infarction), inflammation, and
cigarette smoking. Genetic studies have shown that
plasma fibrinogen levels are significantly elevated in
individuals who are homozygous for the rare B2
allele within the fibrinogen gene. Therefore, fibrinogen may represent an important risk factor under
both genetic and environmental control. Screening
at-risk individuals for the potentially harmful B2
allele might help identify people who should be
closely monitored and who should avoid environmental factors that could accelerate atherosclerosis.
Various lipid and lipoprotein abnormalities at the
protein and gene level have been correlated with the
development of cardiovascular disease.8'9 These disorders are also under environmental and genetic
control. Familial hypoalphalipoproteinemia is an autosomal dominant trait that is a common cause of
high density lipoprotein (HDL) deficiency. It has
been associated with premature cardiovascular disease and strokes.10 Other disorders such as familial
hypercholesterolemia (homozygous form), type III
and type IV hyperlipoproteinemia, and Tangier disease have been associated with premature atherosclerosis and stroke.11-12 As characterization of the
complex genetic pathways responsible for lipid metabolism improves, more high-risk alleles and mutations will be identified.
Epidemiologic Studies
If genetic factors play a role in the etiology of
stroke, one might expect epidemiologic studies to
identify a family history of stroke as a significant risk
factor. Although almost a dozen large-scale studies
reported since 1966 have attempted to analyze this
issue,13"23 they are limited by some intrinsic weaknesses. Most of the studies did not separate strokes
into various subtypes and pathogenic mechanisms,
thereby severely limiting any genetic analysis. For
example, a large hemispheric stroke could be caused
by a cardiac embolism (from atrial fibrillation or
valvular heart disease) or by atherosclerotic occlusion of the internal carotid artery. The resulting
phenotype is the same, but the underlying etiology is
quite different. Likewise, it is unclear if lacunar
strokes should be considered etiologically similar to
carotid occlusion although they share some of the
same risk factors. Some misclassification of stroke
type could have occurred since many of the studies
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were done before computed tomographic (CT) scans
became widely available.
Few of the studies corrected for patients' ages
although it is well known that the risk of stroke
increases significantly with advancing age. When a
similar error was corrected for in the study of families
with Alzheimer's disease, a marked familial aggregation was detected, consistent with an autosomal
dominant trait.
Only four studies used modern statistical multivariate analysis to evaluate the role which standard risk
factors played in determining stroke risk.16-18'21'22 Despite these limitations it is interesting to note that three
of the four studies using multivariate statistical analysis
and correction for age did find a significant contribution of genetic factors to the development of stroke.
These findings must be weighed against the results
of the Honolulu Heart Study, which evaluated the
occurrence of stroke and heart disease in a cohort of
men who migrated from Japan to Hawaii. This study
found that environmental factors were of primary
importance in determining the occurrence of cardiovascular disease.24 However, the results could be
interpreted as showing that environmental factors
modified the expression of the underlying genetic
predisposition for vascular disease by accelerating or
retarding the rate of atherosclerosis.
Since stroke shares many common epidemiologic
and pathogenic features with coronary artery disease
(CAD), studies of the genetics of CAD may provide
clues about common genetic influences. The epidemiologic study of CAD has been underway for over
40 years with many well-described familial associations.25 The presence of CAD in a first degree
relative prior to age 55 increases by tenfold the risk to
other family members.26 In several twin studies of
CAD, most showed a strong genetic component.27-28
Familial associations of high-risk lipid alleles have
also been demonstrated. Although genetic factors
appear to play a major role in determining the risk
and development of CAD, direct comparisons between CAD and stroke are difficult since CAD is a
fairly homogeneous entity and stroke is clinically and
etiologically heterogeneous.
Familial Stroke
An alternative approach to large population-based
studies is to identify specific families with particular
types of stroke. While such familial aggregations are
uncommon, an analysis of such families could provide significant information about the pathogenesis
of stroke in sporadic cases. Also, the study of such
families could lead to the development of larger
pedigrees that could be sufficient for genetic linkage
analysis.
There have been several reports of well-documented
pedigrees with familial cerebral infarction. A French
group has described a large family with an apparent
autosomal dominant disease that presents with strokes
or transient ischemic attacks (TIAs) in the 30s and 40s.
These patients appear to have mostly white matter
infarcts. There is no significant aggregation of risk
factors and no evidence of an inherited coagulopathy.
Angiographic studies have been negative. Head CT or
magnetic resonance imaging (MRI) showed white matter lucency that in some cases was dramatic. This may
be a form of inherited Binswanger's disease or perhaps
a defect in white matter metabolism.29
In 1987 Sonninen and Savontaus30 reported a
51-member family (16 affected) with an inherited
form of multi-infarct dementia. Examination of 14
patients showed a mean age of onset of 46 years and
mean disease duration of 10.6 years. Head CT
showed white matter infarcts that were confirmed on
postmortem examination of one patient.
The familial occurrence of vascular malformations,
particularly arteriovenous malformations (AVM)
and cavernous angiomas, has been reported. In 1985
Boyd et al31 reported four males in two generations
who had AVMs documented by the head CT scan.
Several other cases of apparent familial AVMs have
been noted.32-33 The pattern of inheritance in this
report and others suggests an autosomal dominant
trait, perhaps with variable penetrance. Since few
studies have evaluated asymptomatic relatives of
apparently sporadic cases, the true incidence and
hereditary pattern are unclear.
A study of cavernous malformations by Rigamonti
et al34 found a familial aggregation in 13 of 24
probands. In several asymptomatic at-risk individuals
brain MRI showed lesions consistent with cavernous
malformations. This familial form may be particularly
common among Mexican-American families and appears to be inherited as an autosomal dominant trait,
perhaps with incomplete penetrance. Pettigrew et
al35 reported another large kindred of 75 individuals
with hereditary cavernous hemangiomas.
Intracranial aneurysms have been associated with
several other inherited disorders such as polycystic
kidney disease, Ehlers-Danlos syndrome type IV, and
Marian's syndrome. There have been a total of 177
patients from 74 kindreds with familial aneurysms
reported in the literature.36 A multivariate analysis
showed that intracranial aneurysms in siblings
tended to occur at identical or mirror sites and that
familial aneurysms tended to rupture at smaller sizes.
The exact percentage of cases of aneurysm that are
familial is unclear since asymptomatic relatives would
not usually be studied if the proband had a negative
family history. An autosomal dominant mode of
inheritance has been suggested.36 Several candidate
genes for familial and sporadic intracranial aneurysms are being studied, including type I and type III
collagen. However, in a recent study LeBlanc et al37
failed to identify a collagen defect in some cases of
familial intracranial aneurysm.
A prime example of the successful interaction of
genetic and population research in stroke is the study
of Icelandic amyloid angiopathy. This is an autosomal dominant disease with the onset of severe intracerebral hemorrhages before age 40.38-39 The cerebral vasculature shows depositions of cystatin C, an
Alberts Genetic Aspects of Cerebrovascular Disease
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amyloid-like protein. The cystatin C protein and gene
have been isolated and sequenced.38 Family studies
have shown a specific DNA mutation of the cystatin
C gene in every clinically affected family member.39
While the exact pathophysiology of the defect has not
been clarified, the finding of a disease-specific mutation will accelerate the understanding of the disease
process and offer an accurate tool for genetic counseling. Another recent study by Levy et al40 identified
a pathogenic mutation of the amyloid gene presumed
responsible for hereditary cerebral hemorrhage,
Dutch type.
There have been other scattered reports of genetic
factors underlying the pathogenesis of moyamoya
disease, amyloid angiopathy, and transient global
amnesia.41-43 A recent review described many other
inherited conditions (coagulopathies, malformations,
metabolic disorders) associated with stroke.12
Although the collection of isolated families with
specific stroke types may introduce ascertainment
and population biases into genetic studies, this approach has the advantage of focusing research on a
specific disease while minimizing the influence of a
myriad of risk factors. Because stroke is such a
complex disorder, population-based genetic studies
may not be practical at this time. Directed efforts
using families with a specific stroke type or studying
various candidate genes in a well-defined population
may avoid some of the limitations of past research.
Animal studies of stroke genetics have been limited by a paucity of models with inherited stroke. The
spontaneously hypertensive stroke-prone rat has
been used in most studies, but the overwhelming
genetic influence of the hypertension trait is a limitation. Also, anatomic variations may account for
some of the genetic influences. Two reports have
found evidence for either a recessive trait or a
multifactorial gene effect.44-45
Future Directions
Large-scale epidemiologic studies of stroke have
been attempted in the past with variable results.
Perhaps a more efficient approach would be the
identification and study of kindreds with a familial
aggregation of a particular stroke type. If several
families could be developed, genetic linkage studies
could begin. More sophisticated methods of linkage
analysis such as APM and ARP could be used to
isolate major gene effects, even if extended families
could not be ascertained. If a major gene effect is
identified, apparent sporadic cases could be screened
to determine the frequency of these high-risk alleles.
Once major deleterious genes or alleles are identified, steps to prevent or alter gene expression could
be instituted.
If large population-based studies are to be attempted again, several modifications may improve
patient ascertainment and classification: 1) Identify
patients with precursor lesions prior to becoming
symptomatic. For example, the relatives of probands
with carotid atherosclerosis could be screened by
279
carotid ultrasound. 2) Reclassify stroke types so that
similar phenotypes and pathologic lesions are
grouped together. Patients with CAD may be considered similar to stroke patients with carotid disease.
3) Ascertain families with early onset disease since
they are least likely to be significantly influenced by
the standard risk factors.
In conclusion, the study of genetically complex
diseases such as CAD, cancer, hypertension, and
stroke is now beginning. Rapid advances in molecular genetic techniques and genetic epidemiology have
provided the tools to identify and isolate major gene
effects responsible for these disorders. Understanding these major genes will provide new avenues for
the prevention and treatment of stroke.
Acknowledgments
The author wishes to thank Dr. Lawrence Brass for
assistance in obtaining some reference material and
Dr. Margaret Pericak-Vance for advice in population
genetic studies.
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KEY WORDS • cerebrovascular disorders • genetics
Genetic aspects of cerebrovascular disease.
M J Alberts
Stroke. 1991;22:276-280
doi: 10.1161/01.STR.22.2.276
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