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The Role of Genetic Variation in Haemorrhagic Stroke:

An Update
Das S1,2 and Munshi A3*
1
Institute of Genetics and Hospital for Genetic Diseases,
Osmania University, India
2
Department of Health Sciences, Dr. NTR University of
Health Sciences, India
3
Centre for Human Genetics and Molecular Medicine,
Central University of Punjab, India
*Corresponding author: Anjana Munshi, Centre for
Human Genetics and Molecular Medicine, School of
Health Sciences Central University of Punjab, Bathinda,
Punjab, India
Received: June 06, 2016; Accepted: June 27, 2016;
Published: July 06, 2016

Abstract
Diseases are known to have a genetic background and some diseases can
be rare to common or even restricted to ones family/ lineage/ethnicity. Stroke
is more of a heterogeneous disorder owing to multiple factors affecting its
sudden appearance. Research on ischemic stroke and hemorrhagic stroke has
suggested genetic variations in different genes along with few established risk
factors to lead to its development. However, hemorrhagic stroke is associated
with greater morbidity and mortality as compared to other stroke subtypes
therefore in this review we present an overview on the genetics of hemorrhagic
stroke. The role of some major genes, other associated genes, environmental
risk factors that can possibly contribute to progression of hemorrhagic stroke
has been discussed.
Keywords: Hemorrhagic stroke; Recurrence stroke; Intracerebral
hemorrhage; Subarachnoid hemorrhage; Lobar; Non- lobar intracerebral
hemorrhage

Introduction
Stroke is a complex disorder resulting from an interaction
between a persons genetic background and various environmental
factors. Latest statistics find it to be a leading cause of adult disability
and the fifth leading cause of death with nearly 40% deaths occurring
only among males. Hence, identification of markers for stroke is
required both for risk prediction as well as for intervention to avert
future events. Earlier molecular genetic studies were conducted by
employing linkage studies and using markers such as microsatellites
to identify areas of risk. Stroke is a heterogeneous condition and is
divided into two types called as the ischemic stroke and hemorrhagic
stroke. These 2 types are further divided into various subtypes.
Hemorrhagic stroke
Of the two forms of stroke attack, hemorrhagic stroke is perceived
to be more complex since clinically a well-defined classification for it
is still underway. Nevertheless, few groups have focused on studying
it and report hemorrhagic stroke to be a more deadly form of stroke.
It accounts for almost 13%-20% of all strokes and is associated with
a mortality rate four times higher than that of ischemic stroke.
Depending on the location of hemorrhage this is further subdivided
into extradural, subdural, subarachnoid, intraventricular and
intracerebral hemorrhage. Primary Intracerebral Hemorrhage
(ICH) originates from rupture of small vessels damaged by chronic
hypertension, whereas, secondary intracerebral hemorrhage is
commonly associated with Subarachnoid Hemorrhage (SAH) due
to ruptured intracranial aneurysms or ruptured arteriovenous
malformations. Thus, effects of stroke depend on site and severity of
brain injury with a severe stroke resulting in sudden death. Extensive
progress has been made in understanding the monogenic forms of
stroke but underlying pathogenesis suggests most of the strokes to
be multifactorial in origin. Stroke cases have been reported to be
clustered in families and it is found that 10% of patients suffering with
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ICH have a positive family history of hemorrhagic stroke [1]. Having

a first degree relative with ICH has been suggested to be a high risk
factor for developing the disease and individuals having a first degree
relative with SAH are at seven-fold increased risk of developing SAH
[2,3].
Genetics of hemorrhagic stroke
A considerable number of genetic association studies have
identified a number of candidate genes but there is lack of
reproducibility and uncertainty about the nature and number of genes
involved in hemorrhagic stroke [4]. Additionally, there is a concern on
positive associations being spurious and negative associations to be a
result of inadequate statistical power due to small sample size or other
methodological shortcomings [5,6]. Both candidate gene approaches
and Genome Wide Association Studies (GWAS) have dissected
the role of genetic components in ICH risk. However, GWAS has
emerged as a more relevant tool to study ICH to conduct large scale
genetic investigations. Along with it novel technologies such as nextgeneration sequencing provide an additional avenue for interesting
discoveries regarding genetic contributions to hemorrhagic stroke.
Recent studies suggest on possible genetic links with ICH but in
clinical terms there has been a lack of proper explanation for it. ICH
is more of an acute manifestation of a chronic vasculopathy therefore,
genetic contribution to Cerebral Amyloid Angiopathy (CAA) and
hypertension is more relevant to study while analysing hemorrhagic
stroke genetics [7]. Nevertheless, owing to devastating consequences
of hemorrhagic stroke, it is essential to study the genetic variants that
increase risk of ICH such that knowledge emerging from it assists in
preventive strategies and helps define new therapeutic approaches.
The strongest evidence for genetic association of ICH comes from
a recent GWAS that drew data on SNPs and Neuroimaging data in
a cohort of 791 individuals with ICH and 876 healthy controls and
found a heritability estimate of 44% for overall ICH risk. A substantial

Citation: Das S and Munshi A. The Role of Genetic Variation in Haemorrhagic Stroke: An Update. Austin Neurol.
2016; 1(1): 1003.

Munshi A

difference in heritability for lobar and deep ICH risk was estimated
to be 73% and 34% respectively. Further, 15% of heritability was
found to be mediated by variants in gene encoding Apolipoprotein
E (APOE) and 29% of heritable ICH risk was related to non-APOE
loci [8]. The results from the study on heritability estimates were
comparable to earlier studies made in twin and pedigree studies
[9,10]. APOE E2 and APOE E4 alleles were found to be associated
with increased risk of ICH attributed to CAA (CAA-ICH) [11-13].
Another large scale genetic association study involving 2189 cases
and 4041 controls reported increased risk of lobar ICH at genome
wide significance level while meta-analysis studies have found APOE
E4 to be associated with risk of deep ICH [14].
Potential reigning hypothesis linking APOE with the pathogenetic
mechanism states that APOE E4 enhances A deposition in the
cerebral vasculature and that APOE E2 is a risk factor for hemorrhage
from the amyloid-laden vessels. Studies suggest APOE E4 carriers to
be a risk factor for early age hemorrhage as compared to non-carriers
and also responsible for both CAA and CAA-ICH. APOE E4 has been
lined with acceleration of vascular damage resulting from amyloid
deposition which leads to rupture [11]. The mechanism by which
APOE E4 increases risk of ICH is multifactorial because it is also
responsible for risk of hypertension, a well-known risk factor for ICH.
Additionally E4 allele carriers have an increased total cholesterol level
which is yet another vascular stressor and E2 allele bearers are at an
increased risk of vasculopathic changes such as fibrinoid necrosis that
increases the possibility of ICH. In cases of recurrent ICH, E4 results
in a striking 26 fold increase in recurrent risks as compared to E3
carriers and further an accompanied modulation by circulating lipid
levels especially low-density lipoprotein mediates an essential role in
progression [15-18]. A recent study by Woo, et al. 2013 also states
that statin use conferred a higher risk for lobar ICH among E4/E4
and E2/E4 genotype carriers [19]. Further, a genetic association study
by Das, et al. 2016 reports association for certain genotypic models of
APOE with hemorrhagic stroke vs. controls and hemorrhagic stroke
vs. ischemic stroke [20].
Angiotensin Converting Enzyme (ACE) is yet another gene in
which the Insertion-Deletion polymorphism (I/D) has a shown great
link with hemorrhagic stroke. A recent meta-analysis involving 33
studies reports an association of this polymorphism among Asians
(Chinese, Japanese and Indian) but not among the white population
[21]. ACE I/D polymorphism is known to elevate serum ACE levels
that increase ICH risk by promoting hypertension but a clear cut
mechanistic link between the polymorphism and its role in ICH is
still not clear [22-24]. The DD polymorphism has been linked with
Vasculitides that can damage blood vessels through inflammatory
mechanisms [25]. Few other studies have also linked accumulation
of A particles and elevated risk of ICH owing to possible role in
amyloid pathology [26]. A large meta-analysis reported the positive
association of MTHFR (C677T) gene with ICH and the possible
mechanism might be by accelerating atherosclerosis and promoting
plaque rupture via excessive inflammation and endothelial wall
stress [27,28]. Study among a South Indian population also found
significant association for MTHFR (C677T) CT genotype with
hemorrhagic stroke and ischemic stroke but analysis between the
two types of stroke revealed no difference [29]. Apart from these
three major genes other candidates from case-control studies have
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suggested genes like TUBB1, FGA, LDLR, LPA, IL6, TNF, TGF2,
ENG, IFNE, ERLIN1, TRAPPC and WNK2 to be associated with risk
or conferred protection against ICH risk by participating in different
pathological mechanisms [30-34]. Our group specifically has studied
genetic association between ischemic stroke and hemorrhagic
stroke for a few number of genes and found significant difference
in genotype and allele frequencies for APOE (E2, E3 and E4), ACE
(I/D), CCL-11 (1382A>G), MTHFR (C677T) and E-selectin (S128R)
but found negative association for CRP (1059G>C) [20,24,29,35-37].
Apart from genes and their heritability, environmental factors
that include modifiable risk factor i.e. Blood Pressure (BP) plays a
pivotal role in ICH. A recent study suggests inadequate BP control
to associate with both lobar and non-lobar ICH recurrence and
CAA-related ICH [38,39]. Experimental evidence for hypertension
in CAA- related ICH has been demonstrated in a transgenic mouse
model Tg2576 exhibiting Alzheimerslike pathology. Tg2576 mice
developed signs of stroke with shorter latency with increase in systolic
pressure when treated with angiotension II and LG nitroarginine
methyl ester. This study design combined hypertension with
human A presence that served as a valuable tool to understand the
interaction between two clinical factors in leading to spontaneous
ICH [40]. Further, patients who have suffered ICH develop cognitive
impairment at a higher rate and dementia early after ICH seems
prevalent which is strongly associated with hematoma size and
location [41]. ICH as such has no specific therapy but expansion
of initial hematoma is a marker for poor prognosis. The biological
mechanism of hematoma expansion is not clear but so far the only
marker amenable for treatment in ICH is hematoma expansion
thus serving it as a potential therapeutic target [42]. Smoking is yet
another modifiable risk factor linked to aneurysmal Subarachnoid
Haemorrhage (aSAH) and levels of circulating lipids i.e. serum total
cholesterol and low-density lipoproteins have been found to be
declining 6 months preceding primary ICH independent of statin or
alcohol use. This finding in rate of change in serum lipids suggests
lipid levels to be a potential biomarker for impending cerebral injury
[43,44]. Additionally, differences in underlying vascular disease has
been attributed to etiological factors like age and sex and studies that
find such relevant information can help in providing more specific
treatment options [45]. Thus, it can be said that although genetic
factors do provide certain answers but modulation of these by
environment/lifestyle plays quite an important role in pathogenesis
of hemorrhagic stroke. Hence, studies employing gene-environment
and gene-gene interaction studies have been suggested to introduce a
new approach for evaluating the pathogenesis [46].
Further, major difference in genetics of hemorrhagic stroke and
other forms of stroke has been demonstrated in a study by Dykstra
Aiello, et al. (2015). This study describes genes with Differential
Alternative Splicing (DAS) and pathways unique for ICH as compared
to other ischemic stroke etiologies like cardioembolism, large vessel
atherosclerosis and lacunar stroke. Genes that differentiated ICH
from ischemic stroke aetiologies were reported to be INPP5D, ITA4,
NAV1, PDGFC, CCM2, EXOSC1, EXOSC9 and DGCR8. The biological
functions and networks represented by genes with differentially
expressed exons in each disease group varied and pathways that ICH
genes were mostly related with were protein transport and localization.
Whereas, cardioembolic stroke genes were found to be associated
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with ion binding/transport and cellular assembly, large vessel stroke

with cell death, transcription and chromatin and lacunar stroke with
cellular compromise, cell cycle, cell death and survival [47]. However,
yet another study by Radmanesh, et al. (2015) employing exome
sequencing found no rare coding variants to be associated with ICH
but suggested studies with larger sample size for stronger power [48].
Another study in a rat model reports expression of LncRNAs to be
significantly different as compared to control group which suggests
that LncRNAs to be important in pathophysiological process of SAH.
However, their role in humans needs to be explored for LncRNAs to
act as potential biological prognostic markers [49]. A similar role for
other non-coding RNAs i.e. microRNAs (miRNAs) was explored in
cerebral arteries of rats following SAH. miR-30a and miR-143 were
found to differ with time and with control group of sham- operated
rats [50]. Although these set of experiments in humans and rats
respectively provide a new direction of understanding in molecular
genetics of stroke there replication or consistency in enough human
samples/cohorts remains to be researched owing to spatial and
temporal difference that can vary from patient to patient.

Conclusion
Nevertheless, despite these findings the integrated omics approach
like transcriptomics, epigenomics, proteomics and metabolomics
needs to be explored for further understanding the mechanisms
underlying hemorrhagic stroke [7]. Identification of transcriptome
variants, epigenetic changes, proteome profile and microRNAS can
reveal ICH pathogenesis and individual genetic vulnerability at a
better level and reveal better therapeutic targets. Thus, a few recent
studies have already ventured into these areas but massive efforts that
can consolidate overall knowledge from single positive association
studies, GWAS, whole-genome sequencing with other possible
molecular biology realms in diverse cohorts can help to elucidate
a better pathogenesis of ICH. Currently genetics of hemorrhagic
stroke hasnt received much attention and therefore, a fertile new
area of investigation in neurology is open to both clinicians and basic
researchers. To achieve this, an international massive collaborative
effort that can provide more comprehensive and translating data is
the call of time.

Acknowledgement

Austin Publishing Group

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Munshi et al. All rights are reserved
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Citation: Das S and Munshi A. The Role of Genetic Variation in Haemorrhagic Stroke: An Update. Austin Neurol.
2016; 1(1): 1003.

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