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10 Current Neurovascular Research, 2014, 11, 10-15

Genetic Polymorphism of LDLR (rs688) is Associated with Primary

Intracerebral Hemorrhage

Jiann-Der Lee1,3,*, Kuang-Ming Hsiao3, Tsong-Hai Lee2, Ya-Wen Kuo4, Yen-Chu Huang1, Huan-
Lin Hsu1, Ya-Hui Lin1, Chih-Ying Wu1, Ying-Chih Huang1, Meng Lee1, Hsin-Ta Yang1, Chia-Yu
Hsu1 and Yi-Ting Pan1

1
Department of Neurology, Chang Gung Memorial Hospital at Chiayi, and Chang Gung University, Taiwan
2
Department of Neurology, Chang Gung Memorial Hospital at Taoyuan, and Chang Gung University, Taiwan
3
Department of Life Science, National Chung Cheng University, Chiayi, Taiwan
4
Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, and Department of Nursing,
Changhua Christian Hospital, Taiwan

Abstract: Intracranial hemorrhage is the third most common cause of cerebrovascular disease. Some polymorphisms that
affect clotting factors increase the risk of thrombosis. However, few reports have analyzed the effect of polymorphisms on
the hemostatic state in bleeding disorders. The low-density lipoprotein receptor (LDLR) has been shown to contribute to
factor VIII (FVIII) homeostasis, which represents a link between LDLR and hemostasis. FVIII plays a pivotal role in the
coagulation cascade. Patients with high levels of FVIII are at an increased risk of arterial and venous thrombosis. On the
other hand, patients with insufficient FVIII tend to bleed excessively, such as in hemophilia A. In a previous study,
analysis of the genetic LDLR variant rs688 provided evidence suggesting that genetic polymorphisms of rs688 are
associated with thrombotic cardiovascular diseases. The current study aimed to investigate the potential role of rs688 in
primary intracerebral hemorrhage (PICH). This genetic association study was conducted within an isolated Taiwanese
population (447 PICH patients and 430 controls). Genotypes C/C and C/T were used as the reference genotypes, and the
genotype T/T was found to be associated with a 73% decreased risk of PICH. The preliminary evidence suggests that
genetic polymorphisms of LDLR are associated with PICH.

Keywords: Cerebrovascular disease, Genetic association, Intracerebral hemorrhage, LDLR, Single nucleotide polymorphism,
Stroke.

INTRODUCTION pathogenesis of ICH. A positive history of ICH in first-

Intracerebral hemorrhage (ICH) is the second most
common cause of stroke, following ischemic stroke [1].
Incidence of ICH per 100 000 person-years was 24.2 in
white people, 22.9 in black people, 19.6 in Hispanic people,
and 51.8 in Asian people [2]. Depending on the underlying
cause of bleeding, an ICH is classified as either primary or
secondary. Primary intracerebral hemorrhage (PICH),
accounting for 7888% of all cases, originates from the
spontaneous rupture of small vessels damaged by chronic
hypertension or amyloid angiopathy [3].
ICH is a heterogeneous disease that probably results from
an interaction between various environmental factors and the
genetic background of the patient. Although environmental
factors are important, several lines of evidence support the
hypothesis that genetic factors may contribute to the
*Address correspondence to this author at the Department of Neurology,
Chang Gung Memorial Hospital at Chiayi, and Chang Gung University,
Taiwan, No.6, W. Sec., Jiapu Rd., Puzi City, Chiayi County 613, Taiwan
(R.O.C); Tel: +886 5 3621200; Ext: 2759; Fax: +886 5 3623002;
E-mail: jdlee540908@gmail.com
Received: October 21, 2013 Revised: November 07, 2013 Accepted: November 14, 2013
degree relatives has been reported to be a significant risk
factor for both lobar and non-lobar ICH [4, 5]. Single
nucleotide polymorphism (SNP) on chromosome 9p21
(rs1333040) has been reported to be associated with sporadic
brain arteriovenous malformations [6]. Genes related to
apoptosis (BCL2 and OLFM4) and neutrophil regulation
pathways (LTF, LCN2, CEACAM8 and CRISP3) could be
associated with hemorrhagic transformations after
recombinant t-PA [7]. However genetic polymorphisms of
paraoxonase gene (rs705381 and rs854571) were not
significantly associated with hemorrhagic stroke after the
Bonferroni correction [8]. Associations of candidate genes
involved in the pathway of endothelial dysfunction (ACE),
inflammation markers (IL-6, TNF), vessel wall integrity
(ACE, APOE, neprilysin, endoglin, TGF-1), homocysteine
metabolism (methylenetetrahydrofolate reductase), and
hemostasis (APOE, CD-14, Factor VII and XIII, platelet-
activating factor acetylhydrolase, Factor V Leiden, and
beta1-tubulin, VKORC1) have also been reported [9, 10].
Angiotensin-converting enzyme and apolipoprotein E
(ApoE) gene polymorphisms have also been identified as
risk factors for PICH in Chinese subjects [11, 12].
As with many other complex diseases, a large number of
candidate-gene association studies have attempted to identify

1875-5739/14 $58.00+.00 2014 Bentham Science Publishers

LDLR and Intracerebral Hemorrhage
the genes related to PICH. However, only a few replicable
and robust associations have been reported. The reason for
the inconsistencies among the different studies is unclear.
Results may vary with the genetic setting, method of
approach, demographic variables, and nonparticipation rate.
Candidate genes and PICH have been studied in different
ethnic groups, with heterogeneity in allele frequency across
groups, and this heterogeneity may partially explain the
differences in results.
In our previous study, analysis of the rs688 and rs5925
polymorphisms of LDLR in a Taiwanese population provided
preliminary evidence suggesting that genetic polymorphisms
of LDLR are associated with cerebral infarction [13].
Moreover, rs688 and rs5925 are functional SNPs and have
been identified in silico as exon splicing enhancers (ESE)
using computational methods such as RESCUE-ESE
(http://genes.mit.edu/burgelab/rescue-ese/) [14]. SNPs that
alter ESEs, and thereby exon splicing efficiency, are emerging
as functional variants that are capable of modulating disease
susceptibility [15]. A prior study determined that the minor T
allele in rs688 can neutralize a putative ESE within exon 12
of the LDLR [16]. Moreover, rs688T was found to be
associated with inefficient exon 12 splicing in a human
female liver in vivo, leading to inefficient splicing of LDLR
in minigene-transfected HepG2 cells [16]. LDLR has been
reported to contribute to factor VIII (FVIII) homeostasis [17,
18]. In addition, the rs688 genotype may predict the
occurrence of FVIII coagulant (FVIII: c) activity, because T
alleles are associated with higher FVIII: c levels and
coronary artery disease [18]. Patients with high levels of
FVIII are at an increased risk for arterial and venous
thrombosis [19], while patients with an insufficient amount
of FVIII tend to bleed excessively, as in hemophilia A. In
summary, rs688 may represent a functional LDLR SNP that
modulates LDLR exon-splicing efficiency in vitro and has an
association with decreased LDLR splicing efficiency and
FVIII: c in vivo.
Because genetic polymorphisms of rs688 may modulate
the levels of FVIII and thereby affect blood coagulation, we
hypothesized that certain genetic polymorphisms of rs688
may be associated with different levels of FVIII: c, thereby
influencing the risk of PICH. The aim of the present study
was to characterize the genetic variants of rs688 that may
promote spontaneous bleeding in the brain.
MATERIAL AND METHODS
Selection of Patients and Control Subjects
The study population consisted of 447 patients with a
first episode of nontraumatic PICH who were admitted to
Chang Gung Memorial Hospital. The diagnosis of PICH was
verified for all patients on admission by computed
tomography (CT) or magnetic resonance imaging (MRI)
performed within 24 hours of the onset of symptoms. PICH
was defined as a nontraumatic abrupt onset of severe
headache, altered level of consciousness, and/or focal
neurologic deficit associated with a focal collection of blood
within the brain parenchyma as observed on CT or MRI and
not due to hemorrhagic conversion of a cerebral infarction.
Complete blood picture, blood biochemistry, prothrombin
Current Neurovascular Research, 2014, Vol. 11, No. 1 11
and activated partial thromboplastin time, chest radiography
and electrocardiography were performed. Risk factors (i.e.,
diabetes mellitus [DM], hypercholesterolemia, hypertension
[HTN], current [within six months] and prior smoking) were
defined by history taking. Cases of ICH due to subarachnoid
hemorrhage, traumatic hemorrhage, brain tumor, vascular
anomaly, abnormal platelet count, prolonged prothrombin
time, and prolonged activated partial thromboplastin time
were excluded. We selected 430 control subjects by
reviewing the charts of a population of patients admitted to
the hospital who had no history of vascular, throm-
boembolic, or hemorrhagic diseases during the same period.
This study was performed according to a protocol
approved by the institutional review boards of Chang Gung
Memorial Hospital (ethical license No: 102-0458A3) and the
Declaration of Helsinki, as amended in Venice in 1983. All
study participants provided written informed consent.
Marker Selection and Genotyping
Genotyping of rs688 SNP was achieved by primer
extension of the allele-specific extension products and
matrix-assisted laser desorption/ionization time-of-flight
mass spectroscopy (Sequenom, San Diego, CA).
STATISTICAL METHODS
The genotype frequencies of SNP rs688 were calculated
for each locus and tested for Hardy-Weinberg equilibrium.
Biological and clinical variables were compared between the
PICH patients and controls using the Students t-test and chi-
square test for continuous and categorical variables,
respectively. The clinical characteristics and genotype
distribution in both groups were analyzed univariately for
both groups. To assess the independent contribution of the
genotypes to the PICH group versus the control group,
multivariate logistic regression analyses were performed
adjusted for age, sex, HTN, smoking, triglycerides, total
cholesterol, low-density lipoprotein (LDL) cholesterol and
high-density lipoprotein (HDL) cholesterol. Odds ratios
(ORs) and 95% confidence intervals (CIs) were calculated
from the  coefficients and standard errors. A P value of less
than 0.05 was considered to be statistically significant.
Statistical assessments and analyses of interactions between
genotypes and HTN/smoking were performed using
SNPStats software (http://bioinfo.iconcologia.net/SNPstats)
[20].
RESULTS
This analysis included 447 PICH patients and 430
controls. The clinical profiles of each group are shown in
Table 1. Significant differences were observed between the
control and PICH groups in age, sex, HTN, smoking,
triglycerides, total cholesterol, LDL-cholesterol, and HDL-
cholesterol.
Table 2 shows the SNP rs688 association results for the
PICH sample. This polymorphism was in Hardy-Weinberg
equilibrium in both the control and PICH groups (P = 0.25
and 0.27). Akaikes Information Criterion (AIC) was
calculated for rs688 to decide whether the dominant or
12 Current Neurovascular Research, 2014, Vol. 11, No. 1 Lee et al.

Table 1. Clinical Characteristics.

Normal Controls PICH

Characteristics
(n=430) (n=447)

Age, years (mean SD) 59.414.9 56.113.1 (P=0.001)*

Male sex, % (n) 58.6% (252) 70.9% (317) (P<0.001)*

Hypertension, % (n) 54.7% (235) 93.5% (418) (P<0.001)*

Diabetes mellitus, % (n) 17.0% (73) 18.6% (83) (P=0.538)

Smoking, % (n) 26.5% (114) 36.5% (163) (P=0.002)*

Total cholesterol, mg/dL (mean SD) 197.352.5 180.739.7 (P<0.001)*

Triglyceride, mg/dL (mean SD) 157.4107.8 142.889.4 (P=0.030)*

LDL cholesterol, mg/dL (mean SD) 115.529.0 106.836.0 (P<0.001)*

HDL cholesterol, mg/dL (mean SD) 48.012.6 46.015.5 (P=0.039)*

2
Proportions were compared by  analysis. Means were compared by the Students t test. *P<0.05.
Abbreviations: PICH, primary intracerebral hemorrhage; LDL, low density lipoprotein; HDL, high density lipoprotein

Table 2. LDLR SNP rs688 Association Results in Patients with PICH and Normal Controls.

Normal Controls PICH

rs688 P value
(n=430) (n=447)

CC (%) 68 66

CT (%) 28 32

TT (%) 4 2

TT (vs CC+CT) (OR, 95% CI) 1 0.27 (0.100.79) 0.016

Adjusted by age, sex, hypertension, smoking, triglycerides, total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol.
Abbreviations: PICH, primary intracerebral hemorrhage

Table 3. The Interaction between HTN and rs688 for PICH.

rs688 within HTN

HTN rs688 Normal Controls PICH OR (95% CI)

C/C-C/T 192 28 1.00

No
T/T 3 1 7.81 (0.58-105.72)

C/C-C/T 221 408 1.00

Yes
T/T 14 10 0.20 (0.07-0.61)

Test for interaction in the trend: 0.037

Adjusted by age, sex, smoking, total cholesterol, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol.
Abbreviations: HTN, hypertension; PICH, primary intracerebral hemorrhage

recessive inheritance model fit the data best; that is, a model
containing a low AIC value that would minimize the
expected entropy [20]. Accordingly, the recessive model was
selected. Therefore, ORs associated with the TT genotype
were computed, with use of CC+CT carriers as the reference
group. The distribution of genotypes for rs688 was
significantly different between the control and PICH groups
(OR = 0.27; 95% CI, 0.100.79; P = 0.016) (Table 2).
When subjects do not have HTN, there is no significant
difference in PICH risk between subjects with the T/T and
C/C-C/T genotype. However, in the HTN group, subjects
with the T/T genotype has lower risk of PICH when
compared with subjects with the C/C and C/T genotype (OR
= 0.20, 95% CI = 0.07-0.61) (Table 3). In the non-smoking
group, subjects with the T/T genotype have a lower risk of
PICH when compared with the subjects with the C/C and
C/T genotype (OR = 0.10, 95% CI = 0.02-0.39). Neverthe-
less, in the smoking group, there is no significant difference
in risk of PICH between subjects with the T/T and C/C-C/T
genotype (Table 4).
LDLR and Intracerebral Hemorrhage
Table 4. The Interaction between smoking and rs688 for PICH.
rs688 within smoking
Smoking rs688
C/C-C/T
No
T/T
C/C-C/T
Yes
T/T
Test for interaction in the trend: 0.0094
Adjusted by age, gender, smoking, total cholesterol, triglycerides, low density lipoprotein cholesterol and high density lipoprotein cholesterol
Abbreviations: HTN, hypertension; PICH, primary intracerebral hemorrhage.
DISCUSSION
ICH is a common cause of cerebrovascular disorders.
Median case fatality at one month was 40.4% (range 13.1-
61.0). Furthermore, only 12 and 39 percent of patients
achieve independent function [2]. There are many underlying
pathological conditions associated with ICH, however only a
few reports have assessed the role of coagulation factor
disorders in the pathogenesis of ICH.
LDLR, a cell surface glycoprotein, is responsible for the
binding and uptake of plasma LDL particles, and plays a
critical role in maintaining cellular cholesterol homeostasis
[21]. Polymorphisms at the LDLR locus have been reported
to be associated with ischemic cerebrovascular disease
independently from plasma lipids [13]. In addition, the rs688
genotype can modulate FVIII: c levels and is associated with
the risk of coronary artery disease [18]. LDLR has been
shown to contribute to FVIII homeostasis, which represents
a link between LDLR and hemostasis [17, 18].
FVIII plays an important role in hemostasis. It is an
essential blood clotting factor, and a cofactor for factor IXa
which forms a complex that converts factor X to the
activated form Xa in the presence of Ca2+ and phospholipids.
High FVIII levels are associated with the risk of arterial
thrombosis in coronary heart disease and ischemic stroke
[22, 23]. In contrast, blood plasma FVIII levels needed for a
normal clotting process are lower in hemophilia A, a
hereditary bleeding disorder. Coagulation is the process of
blood clot formation, and disorders of coagulation can lead
to an increased risk of bleeding (hemorrhage) or obstructive
clotting (thrombosis).
The rs688 polymorphism has been reported to predict the
occurrence of FVIII: c, and T alleles have been reported to
associate with higher FVIII: c levels and coronary artery
disease [18]. In this study, the T/T genotype (compared with
C/C and C/T genotypes) was associated with a 73% decrease
in the risk of PICH. These findings are compatible with the
above hypothesis that certain genetic polymorphisms of
rs688 are associated with FVIII.
Rs688 has been empirically identified as an ESE in
silico. Splicing of precursor mRNA is an essential step in
eukaryotic gene expression, and alternative splicing is a
regulated process during gene expression that results in a
Current Neurovascular Research, 2014, Vol. 11, No. 1 13
Normal Controls PICH OR (95% CI)
301 280 1.00
15 4 0.10 (0.02-0.39)
112 156 1.00
2 7 2.38 (0.27-20.79)
single gene coding for multiple proteins. At least 70% of
human genes express multiple mRNAs because of
alternative splicing of exons or exon segments [24].
Abnormal variations in splicing are also implicated in
various diseases, and a large proportion of human genetic
disorders result from splicing variants. Altered splicing can
cause disease directly, modify the severity of the disease
phenotype, or influence disease susceptibility. The prod-
uction of alternatively spliced mRNAs is regulated by a
system of trans-acting proteins that bind to cis-acting sites on
the pre-mRNA itself. The majority of disease-causing
splicing mutations affect critical splicing regulatory signals
in cis (for example, mutation of consensus splice site
sequences at exon-intron boundaries or splicing enhanc-
er/silencer elements within exons or introns) [25].
Serine/arginine-rich (SR) proteins typically promote exon
selection by binding to ESE elements [26].
In brief, ESEs are discrete sequences within exons that
promote both constitutive and regulated splicing. For
example, the minor T allele of rs688 has been found to
disrupt a SRp40 exonic splicing enhancer in exon 12,
causing a modest (10%) reduction in splicing efficiency that
results in the generation of an LDLR transcript lacking exon
12. The exclusion of exon 12 is thought to cause a frameshift
in exon 13, resulting in novel carboxyl terminal sequences
followed by a termination codon [16]. The resulting LDLR
protein would retain the LDL-binding domain encoded by
exons 17, but lack the transmembrane domain encoded by
exons 16 and 17, and hence, would be present as a truncated,
secreted form of LDLR that retains the ability to bind apoE-
containing lipoproteins or FVIII.
The identification of genetic risk factors for PICH has the
potential to improve clinical risk assessment. An important
application of such genetic screening is in decision-making
for chronic anticoagulation therapy. Use of warfarin
increases both the frequency and severity of ICH. Thus, even
at the annual rate of 0.20.6% observed in randomized trials
of conventional-intensity anticoagulation [27], warfarin-
related ICH exerts a major effect on clinical decision-
making. The risk of ICH plays a similarly important role in
other clinical situations where the risks and benefits of
anticoagulation therapy may be finely balanced.
Dabigatran 150 or 110 mg twice a day and warfarin are
effective for stroke prevention in atrial fibrillation. In the
Randomized Evaluation of Long-term Anticoagulant
14 Current Neurovascular Research, 2014, Vol. 11, No. 1
Therapy trial, compared with warfarin, dabigatran 110 mg
twice a day was associated with a lower risk of major
bleeding (2.87% versus 3.57%; P = 0.002), whereas
dabigatran 150 mg twice a day was associated with a similar
risk of major bleeding (3.31% versus 3.57%; P = 0.32) [28].
Taking these results and the results of the current study into
consideration, dabigatran 150mg twice a day should be
prescribed for patients with the T/T genotype because they
have lower hemorrhagic risk and higher thrombotic risk than
patients with the C/C or C/T genotype. In contrast,
dabigatran 110mg twice a day may be reserved for
hypertensive patients with the C/C or C/T genotype who had
an ischemic stroke and atrial fibrillation to reduce the risk of
hemorrhage. Thus, the discovery of genetic variants that alter
individual risks of anticoagulation-related ICH could offer
immediate practical benefits to clinicians when a decision to
start anticoagulation therapy is under consideration.
Statins are widely prescribed for primary and secondary
prevention of ischemic cardiac and cerebrovascular diseases.
However, some clinical trials have suggested that statin use
increases risk of ICH [29, 30]. The mechanism by which
statins amplify the risk of hemorrhagic stroke remains
unclear. However, as statins have been shown to increase the
expression of LDLR [31], we hypothesize that LDLR
upregulation may help clear plasma FVIII and further reduce
FVIII levels. In hypertensive patients with the C/C or C/T
genotype, intake of high doses of statins may reduce the
FVIII levels and increase the risk of ICH. Because of the
relatively high risk of ICH in hypertensive patients with the
C/C or C/T genotype, caution should be exercised before
prescribing high doses of statins for these patients.
A prior history of chronic hypertension is a well-known
risk factor for ICH, and the reported occurrence among ICH
patients varies from 45% to 70% [32]. There is now quite
clear evidence that hypertension is the most powerful risk
factor for ICH. In a case-control study, the adjusted OR for
ICH among hypertensive patients was 2.45 (95%CI, 1.61
3.73) [33]. In the present study, there was no significant
difference in the risk of PICH between subjects with the T/T
and C/C-C/T genotype in the non-HTN group. However, in
the HTN group, subjects with the T/T genotype have a lower
risk of PICH when compared with subjects with the C/C or
C/T genotype (OR = 0.2, 95% CI = 0.07-0.61). This finding
indicates that the T/T genotype may have some protective
effect and reduce the risk of PICH especially when subjects
have HTN.
CONCLUSION
These findings, together with the relevance of these
polymorphisms in thrombotic diseases in our previous study
[13, 18], support the idea that a polymorphism may have
opposite roles in thrombosis and hemorrhage, which may
explain the high frequency of these polymorphisms in the
general population. Different genotypes or haplotypes of
LDLR are associated with different stroke subtypes,
including cerebral infarction and intracerebral hemorrhage,
respectively. Normal hemostasis is designed to promote
balance so that hemorrhage is arrested and inappropriate
thrombosis does not occur. However, in the present study, a
Lee et al.
relationship between PICH and FVIII levels was not proven,
and this will be further evaluated in our future research.
AUTHOR CONTRIBUTIONS
J.L. designed the research, collected data, analyzed and
interpreted the data, performed the statistical analysis, and
wrote the manuscript; K.H. and T.L. designed the research,
collected data, analyzed and interpreted the data, and
critically reviewed the paper; Yen-Chu Huang, H.Y., C.H.,
Y.P. and H.H. performed the research and contributed to
subsequent manuscript discussion; Y.K. and M.L. performed
the statistical analysis and contributed to subsequent
manuscript discussion; Ying-Chih Huang, Y.L. and C.W.
performed the research and contributed to coordination.
ETHICAL STATEMENT
Experiments reported in the article involving human
subjects were in accordance with the ethical standards of the
committee responsible for human experimentation
(institutional and national) and with the Helsinki Declaration
of 1975, as revised in 2008 (http://www.wma.net/en/20activ-
ities/10ethics/10helsinki/).
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest
to declare.
Portions of this study were supported by Chang Gung
Memorial Hospital, Taiwan (CMRPG38138 and CMRPG-
381651).
ACKNOWLEDGEMENTS
The authors wish to thank the other staff at the
Department of Neurology, Chang Gung Memorial Hospital
Linkou Medical Center, and especially the participants in
this study for their valuable contributions.
REFERENCES
[1] Mohr JP, Caplan LR, Melski JW, et al. The Harvard Cooperative
Stroke Registry: a prospective registry. Neurology 1978; 28(8):
754-62.
[2] van Asch CJ, Luitse, MJ, Rinkel GJ, van der Tweel I, Algra A,
Klijn CJ. Incidence, case fatality, and functional outcome of
intracerebral haemorrhage over time, according to age, sex, and
ethnic origin: a systematic review and meta-analysis. Lancet
Neurol 2010; 9(2): 167-76.
[3] Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley
DF. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;
344(19): 1450-60.
[4] Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and
environmental risk factors for intracerebral hemorrhage:
preliminary results of a population-based study. Stroke 2002;
33(5): 1190-5.
[5] Woo D, Sekar P, Chakraborty R, et al. Genetic epidemiology of
intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2005; 14(6):
239-43.
[6] Sturiale CL, Gatto I, Puca A, et al. Association between the
rs1333040 polymorphism on the chromosomal 9p21 locus and
sporadic brain arteriovenous malformations. J Neurol Neurosurg
Psychiatry 2013; 84(9): 1059-62.
LDLR and Intracerebral Hemorrhage
[7] Fernandez-Cadenas I, Del Rio-Espinola A, Domingues-Montanari
S, et al. Genes involved in hemorrhagic transformations that follow
recombinant t-PA treatment in stroke patients. Pharmacogenomics
2013; 14(5): 495-504.
[8] Zhang G, Li W, Li Z, et al. Association between paraoxonase gene
and stroke in the Han Chinese population. BMC Med Genet 2013;
14: 16.
[9] Rost NS, Greenberg SM, Rosand J. The genetic architecture of
intracerebral hemorrhage. Stroke 2008; 39(7): 2166-73.
[10] Liu B, Zhang L, Yang Q. Genetics of intracerebral hemorrhage:
Insights from candidate gene approaches. Neurol India 2012; 60(1):
3-8.
[11] Chen CM, Chen YC, Wu YR, et al. Angiotensin-converting
enzyme polymorphisms and risk of spontaneous deep intracranial
hemorrhage in Taiwan. Eur J Neurol 2008; 15(11): 1206-11.
[12] Zhang R, Wang X, Liu J, et al. Apolipoprotein E gene
polymorphism and the risk of intracerebral hemorrhage in the
Chinese population. Genet Test Mol Biomarkers 2012; 16(1): 63-6.
[13] Lee JD, Lee TH, Kuo YW, et al. Polymorphisms at the LDLR
locus may be associated with ischemic cerebrovascular disease
independent of lipid profile. Curr Neurovasc Res 2012; 9(3): 200-6.
[14] Fairbrother WG, Yeo GW, Yeh R, et al. RESCUE-ESE identifies
candidate exonic splicing enhancers in vertebrate exons. Nucleic
Acids Res 2004; 32: W187-90.
[15] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease.
Genes Dev 2003; 17(4): 419-37.
[16] Zhu H, Tucker HM, Grear KE, et al. A common polymorphism
decreases low-density lipoprotein receptor exon 12 splicing
efficiency and associates with increased cholesterol. Hum Mol
Genet 2007; 16(14): 1765-72.
[17] Bovenschen N, Mertens K, Hu L, Havekes LM, van Vlijmen BJ.
LDL receptor cooperates with LDL receptor-related protein in
regulating plasma levels of coagulation factor VIII in vivo. Blood
2005; 106(3): 906-12.
[18] Martinelli N, Girelli D, Lunghi B, et al. Polymorphisms at LDLR
locus may be associated with coronary artery disease through
modulation of coagulation factor VIII activity and independently
from lipid profile. Blood 2010; 116(25): 5688-97.
[19] Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII
levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol
2001; 21(5): 731-8.
[20] Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web
tool for the analysis of association studies. Bioinformatics 2006;
22(15): 1928-9.
PMID: 24295502
Current Neurovascular Research, 2014, Vol. 11, No. 1 15
[21] Brown MS, Kovanen PT, Goldstein JL. Regulation of plasma
cholesterol by lipoprotein receptors. Science 1981; 212(4495): 628-
35.
[22] Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless, LE.
Prospective study of hemostatic factors and incidence of coronary
heart disease: the Atherosclerosis Risk in Communities (ARIC)
Study. Circulation 1997; 96(4): 1102-8.
[23] Folsom AR, Rosamond WD, Shahar E, et al. Prospective study of
markers of hemostatic function with risk of ischemic stroke. The
Atherosclerosis Risk in Communities (ARIC) Study Investigators.
Circulation 1999; 100(7): 736-42.
[24] Johnson JM, Castle J, Garrett-Engele P, et al. Genome-wide survey
of human alternative pre-mRNA splicing with exon junction
microarrays. Science 2003; 02(5653): 2141-4.
[25] Cartegni L, Chew SL, Krainer AR. Listening to silence and
understanding nonsense: exonic mutations that affect splicing. Nat
Rev Genet 2002; 3(4): 285-98.
[26] Wang Z, Burge CB. Splicing regulation: from a parts list of
regulatory elements to an integrated splicing code. RNA 2008;
14(5): 802-13.
[27] Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning
WJ. Antithrombotic therapy in atrial fibrillation: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest 2004; 126(3 Suppl): 429S-56S.
[28] Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding
with 2 doses of dabigatran compared with warfarin in older and
younger patients with atrial fibrillation: an analysis of the
randomized evaluation of long-term anticoagulant therapy (RE-LY)
trial. Circulation 2011; 123(21): 2363-72.
[29] Amarenco P, Bogousslavsky J, Callahan A, 3rd, et al. High-dose
atorvastatin after stroke or transient ischemic attack. N Engl J Med
2006; 355(6): 549-59.
[30] Goldstein MR, Mascitelli L, Pezzetta F. Hemorrhagic stroke in the
Stroke Prevention by Aggressive Reduction in Cholesterol Levels
study. Neurology 2009; 72(16): 1448; author reply 1448-9.
[31] Pocathikorn A, Taylor RR, Mamotte CD. Atorvastatin increases
expression of low-density lipoprotein receptor mRNA in human
circulating mononuclear cells. Clin Exp Pharmacol Physiol 2010;
37(4): 471-6.
[32] Juvela S, Hillbom M, Palomki H. Risk factors for spontaneous
intracerebral hemorrhage. Stroke 1995; 26(9): 1558-64.
[33] Thrift AG, McNeil JJ, Forbes A, Donnan GA. Three important
subgroups of hypertensive persons at greater risk of intracerebral
hemorrhage. Melbourne Risk Factor Study Group. Hypertension
1998; 31(6): 1223-9.