Review

Genetics of ischaemic stroke

Martin Dichgans

Ischaemic stroke is a heterogeneous multifactorial disorder. Epidemiological data provide substantial evidence for a Lancet Neurol 2007; 6: 149–61
genetic component to the disease, but the extent of predisposition is unknown. Large progress has been made in Department of Neurology,
single-gene disorders associated with ischaemic stroke. The identification of NOTCH3 mutations in patients with Neurologische Klinik, Klinikum
Grosshadern, Ludwig-
cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has led to
Maximilians-University,
new insights on lacunar stroke and small-vessel disease. Studies of sickle-cell disease have drawn attention to the D-81377 München, Germany
importance of modifier genes and of gene–gene interactions in determining stroke risk. They have further highlighted (M Dichgans MD)
a potential role of genetics in predicting stroke risk. Little is known about the genes associated with complex Correspondence to:
multifactorial stroke. There are probably many alleles with small effect sizes. Genetic-association studies on a wide Prof Martin Dichgans
martin.dichgans@med.uni-
range of candidate pathways, such as the haemostatic and inflammatory system, homocysteine metabolism, and the
muenchen.de
renin-angiotensin aldosterone system, suggest a weak but significant effect for several at-risk alleles. Genome-wide
linkage studies in extended pedigrees from Iceland led to the identification of PDE4D and ALOX5AP. Specific
haplotypes in these genes have been shown to confer risk for ischaemic stroke in the Icelandic population, but their
role in other populations is unclear. Advances in high-throughput genotyping and biostatistics have enabled new
study designs, including genome-wide association studies. Their application to ischaemic stroke requires the
collaborative efforts of multiple centres. This approach will contribute to the identification of additional genes, novel
pathways, and eventually novel therapeutic approaches to ischaemic stroke.

Introduction emphasises the importance of stroke subtypes and lends

Stroke is the third most common cause of death and the
most common cause of disability in developed countries.
About 80% of strokes are ischaemic. Atherosclerosis
(large-artery disease), cardioembolism, and small-vessel
disease (lacunar stroke) are by far the most common
causes, but various other mechanisms exist (figure 1).1
Non-modifiable risk factors (age, African and Asian race,
male sex) and acquired risk factors (hypertension, cigarette
smoking, diabetes, atrial fibrillation, and obesity) account
for much of the risk of ischaemic stroke.2 Yet, stroke risk
remains insufficiently explained by these factors.
support to the view that large-vessel stroke and myocardial
infarction share similar pathological mechanisms and
genetic susceptibility.
Further insight has come from studies on intermediate
phenotypes. There is strong evidence, for example, for a
genetic component to atherosclerosis as an independent
trait. Carotid intima-medial wall thickness (IMT)—a
Genes
1 2 3 4 5

Genetic factors and intermediate phenotypes Vascular risk factors Stroke mechanism Infarct size
Ischaemic stroke
Studies in twins, families, and animal models provide and stroke outcome
substantial evidence for a genetic contribution to • Hypertension Artherosclerosis
ischaemic stroke.3,4 However, the extent of genetic • Smoking
(large-artery disease)
predisposition is uncertain. In twins, concordance rates
for the disease were reported to be about 65% greater in • Diabetes Cardioembolism
monozygotic than in dizygotic twins, but most twin (cardiac disease)
• Obesity
studies have been relatively small. In case–control
studies, a family history of stroke was shown to increase •Dyslipidaemia Small-vessel disease
the risk of ischaemic stroke by about 75%,3 which is in
• Homocysteine
line with the data from studies in twins, but a precise Other specific
estimate is difficult to ascertain. Genetic predisposition • Others mechanisms
differs depending on age and stroke subtype. Both twin
and family-history studies suggest a stronger genetic 2
component in stroke patients aged younger than 70 years
than in those who are older.3,5,6 Also, genetic factors seem
Environment
to be more important in large-vessel stroke and small-
vessel stroke than in cryptogenic stroke, and there is no Figure 1: Genetic factors and ischaemic stroke
epidemiological evidence for a genetic component in Genetic factors might affect stroke risk at various levels. They could act through conventional risk factors (1),
cardioembolic stroke.5–7 A common observation in interact with conventional and environmental risk factors (2), or contribute directly to an established stroke
mechanism such as atherosclerosis or small-vessel disease (3). Genetic factors could further affect the latency to
epidemiological studies has been that a family history of stroke (4) or infarct size and stroke outcome (5). Genetic factors might affect stroke risk at various levels. Similarly,
myocardial infarction is more common in large-vessel environmental factors and interactions between genes and the environment could occur at various levels. MR
stroke than in other stroke subtypes.5–7 This finding images were provided by the Department of Neuroradiology, Klinikum Grosshadern.

http://neurology.thelancet.com Vol 6 February 2007 149

 Review

surrogate measure for subclinical atherosclerosis—is
largely controlled by genetics.8 Heritability estimates for
IMT range from about 30% to 60%,9,10 which means that
much of the variability is due to genetic factors.
Importantly, this genetic effect seems largely independent
from known risk factors as most estimates were obtained
while adjusting for demographic and vascular risk
factors. On average, studies enrolling largely participants
with cardiovascular disease reported higher heritabilities
than studies in population-based samples,10 which
emphasises the importance of genetic factors in
cardiovascular disease. Additionally, there is evidence for
a genetic contribution to ischaemic white-matter
lesions—a surrogate measure for cerebral small-vessel
disease. Heritability estimates for cerebral white-matter
lesions have been in the range of 55–70%, again
depending on the population under investigation.11,12
Because of the strong genetic contribution, investigators
have started to use IMT and white-matter-lesion volumes
as targets for genetic studies.13
Genetic factors can act at several levels (figure 1). They
can contribute to conventional risk factors such as hyper-
tension, diabetes, or homocysteine concentrations,14,15
which have a known genetic component. They might
further interact with environmental factors16,17 or
contribute directly to an intermediate phenotype such as
atherosclerosis.18–20 For example, sequence variants in
inflammatory cytokine genes seem to interact with
smoking status to affect atherosclerosis risk. Finally,
genetic factors could affect latency to stroke, infarct size
after vessel occlusion, or stroke outcome.4,21–23
There are many studies investigating potential risk
genes for common multifactorial stroke. However, the
most robust findings have been on single-gene disorders,
which will therefore be discussed first.
Single-gene disorders
Mendelian conditions are an important cause of stroke,
especially in young stroke patients without known risk
factors.24,25 In some disorders stroke is the prevailing
manifestation, whereas in others it is part of a wider
phenotypic spectrum (table 1). Most single-gene disorders
are associated with specific stroke subtypes, which
together with the accompanying systemic features can
lead to diagnosis. The following disorders are especially
relevant in clinical practice and are therefore discussed
in more detail.
CADASIL
Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leucoencephalopathy (CADASIL)
is a heritable small-vessel disease caused by mutations in
NOTCH3.20 The clinical phenotype comprises recurrent
strokes and transient ischaemic attacks, progressive
cognitive impairment, and psychiatric disturbance with
onset usually in the third to sixth decade. About a third of
patients develop migraine with aura.26,27 Neuroimaging
findings are similar to those for sporadic small-vessel
disease. A relatively unique and diagnostically important
feature of CADASIL, however, is bilateral involvement of
the anterior temporal white matter and external capsule
(figure 2).28,29 Strokes involving the territory of a large
artery have occasionally been reported but are probably
coincidental.
NOTCH3 encodes a cell-surface receptor, which has a
role in arterial development and is expressed on vascular

Mode of Gene Stroke mechanism Associated clinical features Diagnostic test

inheritance
CADASIL AD NOTCH3 Small-vessel disease Migraine with aura Mutational screening,
skin biopsy
Fabry’s disease X-linked GAL Large-artery disease and Angiokeratoma, neuropathic pain, acroparaesthesia, hypohydrosis, α-galactosidase activity,
small-vessel disease corneal opacities, cataract, renal failure, cardiac failure mutational screening
Sickle-cell disease AR HBB Large-artery disease, small- Pain crisis, bacterial infection, vaso-occlusive crises, pulmonary and Peripheral blood smear,
vessel disease, haemodynamic abdominal crises, anaemia, myelopathy, seizure electrophoresis, mutational
insufficiency analysis
Homocystinuria AR CBS and others Large-artery disease, Mental retardation, atraumatic dislocation of lenses, skeletal Urine analysis, plasma levels of
cardioembolism, small-vessel abnormalities (Marfan-like), premature atherosclerosis, homocysteine and methionine,
disease, arterial dissection thromboembolic events (mutational screening)
MELAS Maternal Mitochondrial Complex (microvascular and Developmental delay, sensorineural hearing loss, short stature, seizures, Muscle biopsy, mutational
DNA neuronal factors) episodic vomiting, diabetes, migraine-like headache, cognitive decline analysis of mtDNA
Marfan syndrome AD FBN1 Cardioembolism and arterial Pectus carinatum or excavatum, upper- to-lower-segment ratio <0·86 or Clinical diagnosis (mutational
dissection arm-span-to-height ratio >1·5, scoliosis >20%, ectopia lentis, dilation or screening)
dissection of the ascending aorta, lumbosacral dural ectasia
Ehlers-Danlos AD COL3A1 Arterial dissection Easy bruising, thin skin with visible veins, characteristic facial features, Biochemical studies, mutational
syndrome type IV rupture of arteries, uterus, or intestines screening
Pseudoxanthoma AR ABCC6 Large-artery disease and Skin changes (increased elasticity and yellow-orange papular lesions), Skin biopsy, mutational
elasticum small-vessel disease ocular changes (angioid streaks), hypertension screening

AD=autosomal dominant. AR=autosomal recessive. HBB=haemoglobin beta. CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. MELAS=mitochondrial
myopathy, encephalopathy, lactacidosis, and stroke. mtDNA=mitochondrial DNA.

Table 1: Single-gene disorders associated with ischaemic stroke

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smooth-muscle cells. The Notch3 receptor is a heterodimer
composed of a large extracellular fragment and a smaller
transmembrane intracellular fragment. Mutations are
greatly stereotyped in that most, if not all, mutations
change the number of cysteine residues within one of
the extracellular epidermal-growth-factor-like repeat
domains.30,31 There have been single reports of mutations
not affecting cysteine residues,32 but the role of these
sequence variants is controversial. The mutational
spectrum is broad. About 95% of patients have missense
mutations that cluster in exons 3–6.31 Preliminary evidence
suggests that some mutations are associated with a slightly
more aggressive phenotype.27,33–35 In general, however, the
genotype seems to have no major effect on the phenotype.
The mechanisms by which NOTCH3 mutations become
pathogenic are still poorly understood. Most mutations do
not seem to interfere with Notch3 receptor signalling.36
However, studies in patients and transgenic mice have
shown that the mutant Notch3 receptor accumulates in
arteries and precapillaries.37,38 Electron microscopy shows
granular osmiophilic deposits within the vascular basal
lamina, which are specific for CADASIL, are present
throughout the arterial system, and can therefore be used
for diagnostic purposes.39 An important observation has
been that the clinical course and MRI findings can vary
from relatively benign to very severe.26,27 Evidence suggests
that variations in disease severity are due to a modifying
effect of genetic factors distinct from the causative
NOTCH3 mutation.40
Fabry’s disease
Fabry’s disease is an X-linked systemic disorder caused
by deficiency of the lysosomal enzyme α-galactosidase A
(table 1). Deficiency in this enzyme results in progressive
accumulation of glycosphingolipids, particularly
globotriaosylceramide in the myocardium, renal
epithelium, skin, eye, and vasculature. Onset is typically
in childhood or adolescence with acroparaesthesia,
angiokeratoma, or hypohidrosis being common signs.
Systemic complications involving the kidneys, heart, and
brain usually follow in mid-adulthood.
Fabry’s disease is surprisingly common in young stroke
patients. In a large series of young (18–55 years) patients
with cryptogenic stroke 4·9% of men and 2·4% of women
were shown to carry a functionally relevant mutation in
the α-galactosidase gene (GLA).24 Cerebrovascular
symptoms occur from both large-artery disease and
small-vessel disease, with a preference for the posterior
circulation.24,41–43 Small-vessel disease in Fabry’s disease is
associated with white-matter changes and evidence
suggests that the extent of such lesions is affected by
polymorphisms in the genes for interleukin 6, endothelial
nitric oxide synthase, factor V, and protein Z.44 These
findings on potential modifier genes are promising but
await confirmation.
Fabry’s disease may be suspected on the basis of the
associated systemic signs (table 1) and confirmed by
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Figure 2: Characteristic brain MRI changes in CADASIL
Involvement of the anterior temporal white matter (arrow) and external capsule (arrowheads) in a 67 year old
female patient with CADASIL (FLAIR image).
measuring α-galactosidase A activity or by screening for
mutations. In women, measurements of enzyme activity
are less reliable because of skewed inactivation of the
X chromosome in female mutation carriers. The
mutational spectrum is broad. Most patients carry
missense or non-sense mutations in the coding region of
GLA. Enzyme-replacement therapy with recombinant
α-galactosidase A is effective in reducing globotriao-
sylceramide deposition and improving some of the
symptoms.45,46 A benefit on stroke has not been shown, but
neither randomised trial was sufficiently powered to study
this outcome.
Sickle-cell disease
Sickle-cell disease is the most common cause of stroke in
children.25 The disease can be caused by the homozygous
state for haemoglobin S (HbS) or by the compound
heterozygous state with other haemoglobinopathies such
as haemoglobin C (HbC) or α-thalassaemia.47 HbS results
from an aminoacid substitution in the β chain. About 25%
of patients with HbS/HbS and 10% of those with HbS/
HbC will have a stroke by the age of 45 years.48 In patients
with HbS/HbS the incidence of ischaemic stroke is highest
between 2 years and 5 years (0·70 per 100 patient-years)
and lowest between 20 years and 30 years (0·04 per 100
patient-years). Conversely, the risk of haemorrhagic stroke
is highest in the third decade (0·44 per 100 patient-years).48
Stroke recurrence is common. Clinically overt strokes are
typically due to large-artery disease, characterised by
intimal thickening, proliferation of fibroblasts and smooth-
muscle cells, and eventually thrombus formation. This
process is usually confined to the supraclinoid internal
carotid artery and the proximal portions of the middle and
anterior cerebral arteries.49 Ischaemic infarcts are
commonly located in borderzone regions, in particular the
anterior and deep borderzone region.25,50 Apart from overt
stroke, many patients develop silent infarcts.25,51 These
infarcts are small, located in subcortical regions, and
attributed to small-vessel disease.
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A critical component in the pathogenesis of both large-
artery disease and small-vessel disease is an abnormal
interaction between sickled red blood cells and the
vascular endothelium.25,52 Sickled red blood cells tend to
adhere to the endothelium, thus favouring thrombus
formation and vascular occlusion. Endothelial activation
further promotes remodelling of the arterial wall and
vasculopathy.
The risk of stroke in sickle-cell disease seems to be
strongly affected by modifier genes.53–55 In fact, the stroke
phenotype in sickle-cell disease has become a prominent
example of modifying genetic effects in mendelian
traits. An inhibitory effect of fetal haemoglobin (HbF)
on the polymerisation of HbS has been known for many
years. Concentrations of HbF are under genetic control
and have a major effect on sickle-cell disease in general.
A more specific effect on stroke has been identified for
polymorphisms in various genes associated with
inflammation and cell adhesion. Thus, polymorphisms
in the cell-adhesion molecules VCAM and P-selectin,
for example, were shown to be associated with stroke
risk in sickle-cell disease.54,56,57 Also, there is evidence for
a role of the interleukin 4 receptor gene in determining
stroke risk.57
A major methodological step has been the use of Bayesian
networks. By applying such networks to a large number of
single-nucleotide polymorphisms, Sebastiani and
colleagues54 identified 31 single-nucleotide polymorphisms
in 12 genes that were shown to interact with HbF in
modulating stroke risk. The network included P-selectin
and several genes in the transforming growth factor β
(TGF β) pathway, which has been associated with stroke in
other studies. Remarkably, this network accurately predicted
the occurrence of stroke in an independent sample on the
basis of genotyping of just a few single-nucleotide
polymorphisms. These observations draw attention to the
importance of modifier genes in monogenic disorders.
They further emphasise a potential role of genetics in the
prediction of stroke risk. The risk of stroke in sickle-cell
disease can be substantially reduced by transfusion
therapy.25,58 Transcranial ultrasound has been recommended
for use as a screening tool to identify children at high risk
for stroke and criteria have been developed for the initiation
and duration of transfusion therapy.2,58,59 Yet, chronic
transfusion can cause adverse effects and identification of
patients at risk of stroke remains a challenge. In this regard,
screening methods based on genotyping are a potentially
important approach.54
Homocystinuria
Homocystinuria encompasses a group of mostly
autosomal recessive enzyme deficiencies, which cause
high (>100μmol/L) plasma concentrations of homocysteine
and homocystinuria. The disease should be considered in
any child with stroke, mental retardation, atraumatic
(mostly downward) dislocation of the ocular lenses, or
Marfan-like skeletal abnormalities. Homocystinuria must
152
be distinguished from milder (15–100μmol/L) hyper-
homocysteinaemia, which is a risk factor for stroke in the
general population and is associated with deficient dietary
B6, B12, or folate. The most common cause of
homocystinuria is a deficiency of cystathionine beta-
synthase (CBS), a key enzyme in the degradation of
homocysteine.60 More rarely, homocystinuria results from
disturbances in the conversion of homocysteine to
methionine by a pathway that requires the formation of
methylated derivatives of folate and B12.
About 50% of untreated patients with CBS deficiency
have a thromboembolic event by the age of 30 years and
about a third of these events involve the cerebrovascular
system.61 Homocystinuria can cause stroke not only
through atherosclerosis and thromboembolism but also
through small-vessel disease and arterial dissection.62,63
Homocysteine has been shown to injure endothelial cells
and increase smooth-muscle-cell proliferation in vitro.63
Putative factors by which homocysteine might induce
vascular injury further include extracellular matrix
modification, lipoprotein oxidation, and effects on
platelets and coagulation.64 Patients with concurrent
homocystinuria and factor V Leiden have an increased
risk of thrombosis.65
Around a half of the patients with CBS deficiency
respond to B6. Those who respond tend to have a later
onset, a milder phenotype, and a better prognosis than
non-responders.66 The mutational spectrum of CBS
deficiency is broad.67 There are many private mutations
(ie, unique to one family) but some mutations, in
particular Ile278Thr and Gly307Ser, are relatively
common.67,68 An important observation regarding
genotype–phenotype correlations has been that some
mutations, including Ala114Val and Ile278Thr, are
associated with B6 responsiveness whereas others, in
particular Gly307Ser, are associated with B6 resistance.
Early diagnosis of homocystinuria is essential as
complications can be reduced by early treatment.
MELAS
The syndrome of mitochondrial myopathy, enceph-
alopathy, lactic acidosis, and stroke-like episodes (MELAS)
is associated with several mutations in mitochondrial
DNA.69,70 About 80% of patients carry an A to G transition
at position 3243 in the tRNALeu (UUR) gene. The second most
common mutation (T3271C) is found in about 10% of
cases. The relative distribution of mutant and wild-type
mtDNA might vary in different tissues explaining in part
the immense phenotypic diversity of mitochondrial
disorders. MELAS is associated with various symptoms
(table 1). However, monosymptomatic cases with stroke
as the sole manifestation do exist.70
The cerebral lesions underlying stroke-like episodes in
MELAS differ from typical ischaemic infarcts; the cortex
is almost invariably involved. In many cases, lesions are
not limited to vascular territories and there are no
embolic or stenotic lesions on angiography. Also,
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diffusion-weighted MRI may show an increase in the
apparent diffusion coefficient within acute lesions,
suggesting vasogenic rather than cytotoxic oedema.71
These observations point towards mechanisms other
than pure ischaemic infarction. Current hypotheses
include: 1) a disturbance of the blood–brain barrier;
2) impaired autoregulation of cerebral blood flow;72 and
3) primary defects in neuronal oxidative metabolism.
Lesions can spread over time or substantially regress on
subsequent scans.73
Connective tissue disorders
Ischaemic stroke is a well-known complication of several
heritable connective tissue disorders. Marfan’s syndrome
is an autosomal dominant systemic disorder affecting
the musculoskeletal system, cardiovascular system, and
the eye.74 The diagnosis is usually established on clinical
grounds (table 1),75 whereas the role of genetic testing is
limited. Marfan’s syndrome is caused by mutations in a
very large gene (FBN1; 65 exons) and more than 90% of
families have a private mutation, which renders
mutational screening very laborious.76 FBN1 encodes
fibrillin 1, an extracellular matrix protein. Fibrillin 1 is
expressed in many tissues, including the heart and elastic
arteries. It shares homology with TGFβ binding proteins
and there is increasing evidence for a key role of TGFβ
signalling in Marfan’s syndrome.74,77 Cerebrovascular
complications of the disease include transient ischaemic
attacks, ischaemic infarcts, and subdural haematoma. In
a retrospective series on 513 patients, neurovascular
manifestations were associated with cardiac sources of
embolism, in particular prosthetic heart valves, mitral
valve prolapse, and atrial fibrillation, whereas there was
no association with aortic disease or cerebral artery
dissection.78 However, other studies have observed an
association with aortic and cerebral artery dissection.79,80
Further causes of ischaemic stroke include chronic
anticoagulant therapy and perioperative embolic events
in patients undergoing aortic root replacement.81
Ehlers-Danlos syndrome type IV, the vascular type, is
an autosomal dominant disorder resulting from
mutations in COL3A1, the gene for collagen type III.82
The disorder may be suspected on the basis of the
associated clinical features (table 1) and can be confirmed
by mutational screening or biochemical studies on
cultured fibroblasts (synthesis of an abnormal type III
procollagen). The mutational spectrum is broad and
neomutations are common.82 About 50% of the index
cases have no apparent family history. Cerebrovascular
complications are common and include intracranial
aneurysms, arterial dissection, and spontaneous rupture
of large and medium-sized arteries.80,83 In a series of
419 patients, 11% had neurovascular complications.82
Carotid artery dissection and fistulae involving the carotid
artery were the most frequent findings.
Ischaemic stroke has also been recognised as a
complication of osteogenesis imperfecta and
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pseudoxanthoma elasticum,80 which is associated with
stenotic lesions of the distal carotid artery and with small-
vessel disease (table 1).80,84
Moyamoya disease
Moyamoya disease is a chronic progressive syndrome
that is characterised by bilateral occlusion of the terminal
carotid artery in association with telangiectatic vessels at
the base of the brain.85 The disease is uncommon in non-
Asian populations whereas its prevalence in Japan is
estimated to be three or more in 100 000. The most
frequent manifestations in childhood are transient
ischaemic attack, ischaemic stroke, and epileptic seizures.
Rupture of telangiectatic vessels causes intracranial
haemorrhage—the main manifestation in patients older
than 30 years.85,86 About 10% of moyamoya cases occur as
familial cases, but the pattern of inheritance is not
clear.87,88 Both polygenic inheritance and an autosomal
dominant mode of transmission with incomplete
penetrance have been suggested. Moyamoya disease has
been linked to genetic loci on chromosomes 3p, 8q, and
17q89–91 and moyamoya-like changes have been described
in association with a variety of single-gene disorders,
including sickle-cell disease, pseudoxanthoma elasticum,
and neurofibromatosis type 1.
Miscellaneous
Ischaemic stroke can occur as a complication of several
heritable cardiomyopathies,92,93 dysrhythmias,94 haem-
oglobinopathies,95 coagulopathies,96,97 dyslipidaemias,98
and vasculopathies.99–101 In some cases an association with
stroke has been firmly established.93 In many others an
association is less well documented or a matter of
controversy. A detailed discussion of these disorders is
beyond the scope of this article. Most of them are covered
by specific reviews.92,94,97,98
Common multifactorial stroke and genetic risk
factors for ischaemic stroke
The genetic contribution to common multifactorial
stroke seems to be polygenic. Most likely, there are many
alleles with small effect sizes (relative risk <1·5). However,
because of their wide distribution, on a population basis
the impact on stroke is large. It is increasingly recognised
that the effects of some alleles are limited to one or few
stroke subtypes (figure 1) and that effect sizes may vary
depending on sex and ethnic origin.19,102
Most previous studies investigating genetic risk factors
for human stroke have taken a candidate gene approach
using case–control methodologies. To be reliably
detected, small relative risks require large sample sizes,
probably in the order of 1000 patients or more.103,104
However, few studies have achieved such numbers. This
difficulty, together with differences in sample
characteristics and study design, could explain much of
the inconsistency between studies. Table 2 and the
webtable summarise the results from case–control See Online for webtable
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Polymorphism Genetic model Study Patients’ characteristics Cases (carriers/ Controls (carriers/ OR (95% CI) (unadjusted)
individuals) individuals)
MTHFR C677T Recessive 106 Meta-analysis (22 studies) 463/3387 630/4597 1·24 (1·08–1·42)
108 IS (women, 18–49 years) 26/193 69/764 1·5 (0·9–2·6)
63 SVD (lacunar S) 33/170 16/170 2·72 (1·32–5·60)
109 IS 14/146 2/55 2·81 (0·61–12·99)
110 Cryptogenic IS/TIA (<50 years) 9/93 26/186 0·66 (0·33–1·47)
ACE Ins/Del Recessive 106 Meta-analysis (11 studies) 903/2990 2993/11 305 1·21 (1·08–1·35)
114 IS (18–85 years) 153/456 149/459 1·05 (0·80–1·38)
115 IS (without CES, 50–97 years) 116/215 111/236 1·3 (0·9–1·9)
116 IS (without CES) 48/108 37/79 0·95 (0·69–1·30)
Factor V Leiden Arg506Gln Dominant 106 Meta-analysis (26 studies) 287/4588 901/13 798 1·33 (1·12–1·58)
119 IS/TIA (<60 years) 29/468 30/468 0·96 (0·57–1·63)
120 Cryptogenic IS/TIA with PFO 13/220 21/362 1·02 (0·50–2·10)
120 IS or TIA 11/196 21/362 0·97 (0·46–2·05)
108 IS (women, 18–49 years) 14/179 42/763 1·8 (0·9–3·6)
121 IS (15–45 years) 4/115 10/180 1·62 (0·46–4·06)
122 IS (>80 years) 1/114 6/150 0·22 (0·03–1·85)
110 Cryptogenic IS/TIA (<50 years) 15/93 13/186 3·19 (1·38–7·39)
123 Cryptogenic IS with PFO 4/57 1/104 7·8 (0·85–71·31)
124 Cryptogenic IS (<50 years) 2/49 5/294 2·62 (0·49–13·95)
Prothrombin G20210A Dominant 106 Meta-analysis (19 studies) 105/3028 210/7131 1·44 (1·11–1·86)
108 IS (women, 18–49 years) 5/188 18/763 1·0 (0·3–3·0)
121 IS (15–45 years) 8/115 10/180 1·27 (0·48–3·35)
122 IS (>80 years) 6/114 5/150 1·61 (0·48–5·42)
110 Cryptogenic IS/TIA (<50 years) 1/93 6/186 0·33 (0·04–2·75)
123 Cryptogenic IS with PFO 2/57 0*/104 1·0 (1·0–1·1)
124 Cryptogenic IS <50 years 4/49 7/294 3·75 (1·05–13·34)
PAI1 4G/5G Recessive 106 Meta-analysis (4 studies) nr/842 nr/1189 1·47 (1·13–1·92)
125 IS (18–69 years) 131/600 134/600 0·97 (0·74–1·28)
126 IS (25–74 years) 43/222 107/542 0·98 (0·66–1·45)
127 IS (18–75 years) 29/123 29/123 1·0 (0·6–1·8)
126 IS (25–74 years) 14/89 42/218 0·78 (0·40–1·52)

Candidate genes and polymorphisms were selected if there was at least one positive study reporting a significant association with ischaemic stroke and if the total number of studies was two or more. Studies
were selected if they fulfilled the following criteria (adopted from reference 106): 1) population consists of predominantly white patients; 2) population consists mainly of adults (age >18 years); 3) use of
neuroimaging (CT or MRI); 4) genotype frequencies for ischaemic stroke reported. Studies on populations already included in reference 106 are not included. MTHFR=methylenete-tetrahydrofolate reductase.
IS=ischaemic stroke. SVD=small-vessel disease. S=stroke. TIA=transient ischaemic attack. CES=cardioembolic stroke. LVD=large-vessel disease. PFO=patent foramen ovale. nr=not reported. *p set at 0·5 to
calculate unadjusted odds ratio.

Table 2: Selected candidate gene case–control association studies in ischaemic stroke

association studies on ischaemic stroke in predominantly
white populations. Here we focus on selected pathways
and candidate genes.
Homocysteine metabolism
Mild to moderate increases in plasma homocysteine are
associated with a heightened risk of stroke.105 A common
polymorphism (C677T) in the gene encoding 5.10-methyl
enetetrahydrofolate reductase (MTHFR), a critical enzyme
in homocysteine catabolism, has been shown to be
associated with both raised homocysteine concentrations
and increased stroke risk. C677T results in an amino-acid
substitution and renders the enzyme thermolabile. The
TT genotype, which is present in about 10% of the
population, increases total homocysteine by about 20%.
In a meta-analysis15 involving more than 15 000 people
without cardiovascular risk, the weighted mean difference
in plasma homocysteine between individuals with the TT
and CC genotype was 1·93 μmol/L.15 This difference
corresponds to an expected odds ratio for overall stroke of
about 1·20.105 In a meta-analysis on the relation between
the C677T polymorphism and stroke the observed odds
ratio for overall stroke was 1·26 for TT vs CC.15 The effect
seems to be largely independent of ethnic background
and a similar odds ratio was found for ischaemic stroke
only (table 2),106 with a possible gene-dose effect for the
T allele.107 Few authors have looked at ischaemic stroke
subtypes or intermediate phenotypes.8,63,108–110 In one study,
both homocysteine concentrations and the MTHFR
C677T allele were shown to be significant risk factors for

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small-vessel disease,63 adding to the notion that the
association with stroke is not limited to large-artery
disease. Overall, the TT genotype of the C677T
polymorphism has been established as a moderate risk
factor for ischaemic stroke and the increase in risk seems
to be largely mediated through raised homocysteine
concentrations (figure 1). Whether homocysteine-
lowering treatment can reduce the risk of stroke is still
unclear.111,112
Renin-angiotensin-aldosterone system
Evidence suggests that genetic variation in the renin-
angiotensin-aldosterone system (RAAS) contributes to
the risk of ischaemic stroke. Among the various sequence
variations in RAAS, the insertion/deletion (I/D)
polymorphism in angiotensin converting enzyme (ACE)
is the most extensively studied. ACE produces angiotensin
II and catabolises bradykinin thereby affecting vascular
tone, endothelial function, and smooth-muscle-cell
proliferation. RAAS has a well-documented effect on
systemic blood pressure. Mean ACE activity concentration
in DD carriers are around twice those found in II carriers.
Thus, the I/D polymorphism has become a strong
candidate for cardiovascular risk.113
In a meta-analysis106 including 2990 predominantly
white patients and 11 305 controls, the DD genotype was
shown to confer a small but significant risk of ischaemic
stroke (odds ratio 1·21; 95% CI 1·08–1·35). Since then,
there have been several studies with non-significant
results (table 2).114–116 However, none of them was powered
to detect a 20% risk increase. On balance, the available
data suggest that any effect of the D allele on ischaemic
stroke is small. The effect of the I/D polymorphism on
ischaemic stroke subtypes,95 intermediate phenotypes,8
and blood pressure113 has been explored in several small
studies, but with variable results.
Recent findings suggest that the A1166C polymorphism
of the angiotensin II type-1-receptor gene is associated
with ischaemic stroke (webtable). However, the number
of available studies is small and in one study the
association with ischaemic stroke disappeared when
adjusting for risk factors.114 A1166C has been associated
with several vascular phenotypes and it seems possible
that this polymorphism acts by affecting blood pressure.
The angiotensinogen (AGT) gene was investigated in
several studies with conflicting results (webtable).117 A
potentially interesting observation, however, is the
reported association between an AGT promoter haplotype
and cerebral small-vessel disease.118
Haemostatic system
Prothrombotic states, such as activated protein C
resistance and the underlying Factor V Leiden
polymorphism, are an established risk factor for venous
thrombosis but their role in ischaemic stroke is still
debated. According to a recent meta-analysis,106 the factor
V Leiden Arg506Gly polymorphism, the prothrombin
http://neurology.thelancet.com Vol 6 February 2007
Review
G20210A polymorphism, and the plasminogen activator
inhibitor 1 (PAI1) 4G/5G polymorphism all confer a small
but significant risk for ischaemic stroke (table 2).
However, most large studies have not found an association
between prothrombotic states and overall incidence of
ischaemic stroke. Also, in the meantime several negative
studies have been published including studies on
cryptogenic stroke (table 2, webtable).108,110,119–127 On balance,
prothrombotic states might be responsible for stroke in
some younger patients128 and in those with additional risk
factors (table 2).108,119 However, there is less evidence for a
role of prothrombotic states in unselected patients with
common multifactorial stroke.
Phosphodiesterase 4D
A major discovery has been that variation in the
phosphodiesterase 4D (PDE4D) gene is associated with
ischaemic stroke in the Icelandic population.129 PDE4D
resides within a 20cM region on chromosome 5q12
(STRK1), which had previously been identified through
genome-wide linkage analysis. In association analyses
several single-nucleotide polymorphisms in PDE4D
were associated with the combined phenotype of
cardiogenic and carotid stroke. Furthermore, an at-risk
haplotype, comprising microsatellite AC008818-1 and
SNP45 was shown to confer a relative risk of 1·5 for the
combined phenotype.129 PDE4D degrades second
messenger cAMP, which is a key signal transduction
molecule in multiple cell types, including vascular
endothelial, smooth muscle, and inflammatory cells.
Since associations were limited to cardiogenic and
carotid stroke it was suggested that PDE4D acts through
atherosclerosis. Yet, a subsequent study found no
association between various single-nucleotide
polymorphisms and IMT.130 Replication studies in other
populations including Asians and blacks have yielded
variable results.17,130–140 Several studies reported nominally
significant associations between single-nucleotide
polymorphisms or haplotypes and stroke. However,
there is much heterogeneity with regard to the associated
genetic variants and stroke subtypes (table 3).141 This
heterogeneity could be due in part to different study
designs. Also, it seems possible that the effect of PDE4D
on stroke varies between populations depending on
different genetic backgrounds and environmental
influences.17 Despite extensive genotyping of the PDE4D
gene region, the disease-causing genetic variant has not
been identified so far. Yet, there is increasing evidence
that the STRK1 locus contributes to the risk of ischaemic
stroke.132
ALOX5AP and the leukotriene pathway
ALOX5AP is another gene that has been discovered
through genome-wide linkage analysis. A common
haplotype (HapA) in ALOX5AP is associated with a
1·8-fold increased risk of myocardial infarction and a
1·7-fold increased risk of stroke in the Icelandic
155
 Review

Reference Study design Study population (number of individuals) Findings*

129 CC Iceland: stroke+TIA (864) / CBC (908) Large-artery stroke and cardioembolic stroke combined: 45,41,87,89,56, AC008818-1, haplotype
Large-artery stroke: 83, DG5S397
Cardioembolic stroke: AC008818-1
131 CC Germany: IS (601) / CBC (736) No significant associations
130 CC UK: IS (737) / CBC (933) Large artery stroke: 19,87
Cardioembolic stroke: 2,13,14,15,20,26
130 CC Germany: CBS (1000) for IMT No significant association with IMT and Carotid plaque
132 Linkage Sweden: 56 families with stroke Linkage to PDE4D region (two linkage peaks)
132 CC Sweden: stroke (275) / CBC (550) No significant associations
133 Linkage USA: 104 families with IS No Linkage to PDE4D region
133 CC USA: IS (377) / C (263) Ischaemic stroke: 56,83, haplotype
Large-artery stroke : 45,83
Cardioembolic stroke: 45
134 CC Netherlands: IS (88) / CBC (190) Small vessel stroke: 39,45 (only in inbred individuals)
135 CC Pakistan: IS (200) / CBC (250) Ischaemic stroke: 83
136 CC Japan: non-CE IS (208) / Outpatients (270) Non-cardioembolic ischaemic stroke: haplotype
137 CC USA: (357) / CBC (303) Ischaemic stroke: 41 (only in whites), haplotype (in whites and blacks)
Cardioembolic stroke: 87 and haplotype (whites and blacks); 41 (only in whites), 83 and 89 (only in blacks)
Small-vessel stroke: haplotype (only in whites)
Cryptogenic stroke: haplotype (in whites and blacks)
138 CC Germany: IS (1181) / CBC (1569) No significant associations
No significant associations
139 CC USA: woman with IS (248) / CBC (560) Ischaemic stroke: 9,42,219,220, AC008818-1 (in non-hypertensives), 175 (in hypertensives), haplotypes
140 CC USA: male incident IS (259) / C (259) Ischaemic stroke: 56 (all ischaemic stroke); 42,45,56 (subjects without baseline hypertension)
17 CC USA: women with IS (224) / CBC (221) Ischaemic stroke: rs918592,83,89,42, rs1498606 (all ischemic stroke), rs918592 (current smoking, dose effect)
Large-artery stroke: rs918592
Small-vessel stroke: rs918592
Cryptogenic stroke: rs918592

CC=case–contol study. TIA=transient ischaemic attack. CBC=community based controls. CBS=community based sample. IS=ischaemic stroke. IMT=intima-media thickness. C=controls. *Numbers refer to single
nucleotide polymorphisms (SNPs) and microsatellite markers that were significantly associated with the respective phenotype. SNPs are labelled according to reference 129.

Table 3: The PDE4D gene and ischaemic stroke

population.19 The association was stronger in men than
women and was significant for both ischaemic and
haemorrhagic stroke. The association between HapA and
ischaemic stroke was subsequently replicated in the
Scottish population, which shares a common ancestry
with the Icelandic population.142 Studies in other
populations reported no association between HapA or
other haplotypes and ischaemic stroke.131,133,143 However, in
a German sample several single-nucleotide
polymorphisms including one out of four single-
nucleotide polymorphisms constituting HapA were
associated with ischaemic stroke. ALOX5AP encodes 5-
lipoxygenase activating protein (FLAP), an important
component of the leukotriene pathway. Leukotrienes are
proinflammatory mediators that are implicated in the
pathogenesis and progression of atherosclerosis.144 Only
recently, genetic variation in another gene involved in
leukotriene biosynthesis, the LTA4 hydrolase gene, was
shown to confer risk for myocardial infarction, especially
in patients with previous stroke or peripheral artery
disease.102 These findings emphasise the importance of
the leukotriene pathway in stroke. The importance of
ALOX5AP for specific stroke subtypes remains to be
determined.
Other candidate pathways and genes
There is a long list of candidate gene pathways and genes
that have been studied for a possible association with
ischaemic stroke. Among the most widely investigated
genes are those involved in inflammation (eg,
interleukin 1, interleukin 6, TNFα, toll-like receptor 4, P-
selectin and E-selectin, C-reactive protein), lipid
metabolism (eg, apolipoprotein E, paraoxonase, epoxide
hydrolase), nitric oxide release, and extracellular matrix
(matrix metalloproteinases). Many of them are listed in
the webtable or discussed in reviews.106,145 In most cases,
however, findings were either negative or could not be
replicated in subsequent studies.
Animal data
Experimental crossbreeding in an inbred strain of
hypertensive rats, which are spontaneously hypertensive
and prone to stroke, has led to the identification of three
major genetic loci that affect stroke risk in these animals.4,21
Str1, Str2, and Str3 were identified through a genome-
wide screening process with quantitative locus mapping
in F2 crosses. All three loci were shown to affect the time
to stroke onset in stroke-prone spontaneously hypertensive
rats fed a stroke-permissive diet.21 The Str2 locus was later

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identified in an independent study as a risk locus for
infarct volume after occlusion of the middle cerebral
artery.4 Str2 colocalises with the gene for atrial natriuretic
peptide (ANP) on rat chromosome 5. Yet, the role of the
ANP gene in ischaemic stroke is still unclear both in rats
and in human beings (webtable). Also, the genetic
variants underlying STR1, STR2, and STR3 remain to be
identified.
Another genetic approach, besides experimental
crossbreeding, has been the targeted disruption of genes.
For example, mice deficient in neuronal nitric oxide
synthase have been shown to develop smaller infarcts
and less severe functional deficits than control animals
following occlusion of the middle cerebral artery.146 These
studies have helped in understanding the mechanism of
ischaemic stroke and in defining candidate genes for
genetic association studies in human beings. However,
they are less well suited to identify naturally occurring
risk alleles for stroke.
Future directions
The technologies for high-throughput genotyping are
rapidly developing as are the statistical methods to
analyse increasingly complex data. The technical
developments are likely to outpace the collection of large
carefully phenotyped samples. The future of stroke
genetics will therefore depend on the samples available
and on close collaborations between clinicians and
geneticists.
Association-based methods are a powerful instrument
to identify small relative risks. In this respect they are
particularly suited to address common multifactorial
stroke. The candidate gene approach remains a valid
strategy and there are several means by which the power
of such studies can be improved.103,104 Critical issues
include the selection of candidate genes and appropriate
phenotypes, the phenotyping protocols, sample-size
issues, and replication in independent cohorts. These
aspects have been the subject of recent reviews.103,104
Comprehensive analyses of whole genes with genotyping
of multiple single-nucleotide polymorphisms and
haplotype-based analyses have started to replace small
studies on single polymorphisms.19,129 The identification
of PDE4D as a risk gene for stroke provides a good
example of the shift in paradigms and has drawn
attention to the complex associations between at-risk
alleles, associated markers, and associated haplotypes
within and across populations. Because of the
heterogeneity of stroke, analyses according to stroke
subtypes are essential. Interactions with environmental
risk factors will need to be considered as there is evidence
for such interplay in stroke. Also, some genes are likely
to interact in determining stroke risk and researchers
have started to look at epistatic (gene–gene) interactions.
However, such studies make great demands on sample
size. At any rate, replication of novel findings in different
cohorts and settings remains the key.
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Review
Because of the modest success of candidate gene
studies there is a growing interest in systematic
hypothesis-free approaches. Genome-wide studies using
100 000 to 500 000 single-nucleotide polymorphisms
have become technically possible but are a major
challenge in terms of resources and study design. Such
studies require the collaborative effort of multiple centres
and the construction of large databases containing
clinical and epidemiological data.
Linkage-based methods are the strategy of choice when
analysing monogenic disorders and there are several
disorders that await gene identification.99–101 Linkage-
based methods can also be applied to common
multifactorial stroke129,147 and studies like the siblings with
ischaemic stroke study (SWISS) have taken this
approach.132,148 The principles of linkage and association
may further be combined in a single test. This is done in
the transmission disequilibrium test and the sibling
transmission disequilibrium test, which use internal
controls (parents or siblings). However, there are a
number of challenges to the application of linkage-based
methods to complex disorders.149
Analysis of intermediate phenotypes such as IMT has
some advantages over the analysis of complex endpoints
such as stroke.8 For example, IMT is associated with a
single pathology (atherosclerosis) rather than multiple
causes, which increases homogeneity and power. Also,
IMT is a quantitative trait, which allows more powerful
statistical methods to be applied. Yet, any findings for
IMT will need to be separately assessed for their effect on
stroke. Because of a stronger genetic component in
young patients, focusing on juvenile stroke seems
especially promising, but recruiting large numbers is
difficult in such a selected population. In conclusion,
there are various strategies that should be regarded as
complementary.
Recently, pharmacogenetics, which investigates
genetically determined variations in response to drugs,
has emerged as a promising research area. Thus, for
example, polymorphisms in the genes for the hepatic
microsomal enzyme P450 2C9 (CYP2C9) and for vitamin
K epoxide reductase complex 1 (VKORC1) have been
shown to strongly affect individual sensitivity to
warfarin.150,151 Also, recent trialists have started to stratify
patients according to their genotypes.152 The idea behind
these studies is to beneficially affect patient safety and
individual treatment strategies, but the transition into
clinical practice has not yet been made. Genetic testing
has become a valuable tool in diagnosing single-gene
disorders associated with ischaemic stroke, whereas it is
currently not recommended in patients with common
multifactorial stroke.
Conclusion
Much progress has been made in the identification of
genes for mendelian conditions associated with stroke.
However, comparatively little is known about the genes
157
 Review
Search strategy and selection criteria
References for this review were identified by searches of
PubMed from 1966 to September, 2006, by combinations of
the terms “stroke”, “ischaemic”, “gene”, “mutation”,
“polymorphism”, and “association”. Articles were also
identified through searches of the author’s own files. Selection
of material for inclusion was based on quality and relevance.
involved in multifactorial stroke. The identification of
PDE4D and ALOX5AP as risk genes for ischaemic stroke
in the Icelandic population represents a breakthrough,
but the role of these genes in other populations is less
clear. There are various methodological approaches, yet
careful phenotyping and large sample sizes remain the
key. Collaborative efforts from multiple centres are
needed to elucidate the genetic basis of common
multifactorial ischaemic stroke.
Conflicts of interest
I have no conflicts of interest.
Acknowledgments
I thank Michael O’Sullivan for critically reading the manuscript and for
helpful comments. I am supported by the Deutsche
Forschungsgemeinschaft (SFB 596/TPA4). No funding body had a role
in the preparation of the review or in the decision to submit it for
publication.
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