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Table 1 continued
Reference Gene Polymorphism Methodology Phenotype Results Comments
Corral et al., 2000
XIII Val34Leu 116 patients PICH Negative –
Gemmati et al., 2001
XIII Val34Leu 130 patients PICH Positive OR 1.7, 95% CI 1.16–2.51; p=0.009
Reiner et al., 2001
XIII Val34Leu 42 patients Women aged <45 Negative –
XIII Tyr204Phe 345 controls years with PICH Positive OR 2.09, 95% CI 1.1–7.5
XIII Pro564Leu Positive OR 4.3, 95% CI 1.4–1.7
PAI -675 4G/5G Negative –
Cho et al., 2002
XIII Val34Leu 58 patients PICH Negative –
Endler et al., 2003
XIII Val34Leu 94 patients PICH Negative –
Corral et al., 2001
F-V leiden Leiden 201 patients PICH Positive OR 0.19, 95% CI 0.03–0.95
F-II 20210A 201 controls Negative –
F-VII -323 D/I Positive OR 1.54, 95% CI 1.03–2.72
XIII Val34Leu Negative –
Greisenegger et al., 2007
F-VII -401G/T, -402 G/A 85 patients PICH Negative –
Obach et al., 2006
Protein Z c.573-79G/A 156 patients PICH Negative –
Munoz et al., 2007
GAS6 8 variants 199 patients PICH Negative –
Li et al., 2003
MTHFR C677T 503 patients PICH Negative –
McCarron et al., 2003
IL-1a (-899) C/T 42 patients CAA-related PICH Negative –
Strand et al., 2007
OPG -1181G/C, -950T/C 61 patients PICH Positive -1181C/C genotype: OR 6.04,
773 controls 95% CI 1.71–21.29; p=0.005
IL-6 -174G/C Negative –
Strand et al., 2007
ESR1 c.454-397T/C 61 patients PICH Positive c.454-397T/T genotype: OR 3.94,
773 controls 95% CI 1.54–10.03
c.454-351A/G Negative –
Xu et al., 2008
PON2 C311S, G148A 150 patients PICH Negative –
CAA = cerebral amyloid angiopathy; CI = confidence interval; OR = odds ratio; PICH = primary intracranial haemorrhage; IL = interleukin.
ischaemic attacks, lacunar strokes and subcortical dementia. e4 allele increases Aβ deposition in the cerebral vasculature in a dose-
Magnetic resonance imaging reveals extensive peri-ventricular white dependent manner.
The ε2 allele is associated with vasculopathic
matter leucoencephalopathy and the presence of microbleeds, changes in amyloid-laden vessels and rupture.
It has also been
predominantly in subcortical areas and the thalamus, detected on documented that ε2 and ε4 alleles of the ApoE gene are risk factors for
T2-weighted gradient echo imaging. Microbleeds can be present in the occurrence of lobar PICH, probably due to the presence of cerebral
31–69% of patients with CADASIL.
It was found that PICH can occur amyloid angiopathy in the carriers of these alleles.
In addition, the e4
in 25% of symptomatic patients with CADASIL, and this is closely allele was associated with earlier age at onset of CAA-related PICH
related to the number of cerebral microbleeds.
with warfarin-related PICH.
ε2 and ε4 allele carriers are also at
increased risk of recurrent haemorrhage compared with ε3 carriers.
Moreover, the presence of the e4 allele was linked to poor outcome of
It was found that primary intracerebral
However, other studies did not find any association
between ApoE polymorphism and PICH.
In a recent meta-analysis,
haemorrhage can occur in 25% of
the ε2 allele was found to be an independent risk factor for PICH (odds
symptomatic patients with CADASIL, and
ratio [OR] 1.32, 95% confidence interval [CI] 1.01–1.74), whereas ε4
genotypes were not (OR 1.16, 95% CI 0.93–1.44).
this is closely related to the number of
An interesting association between a haplotype in the vitamin K
epoxidase reductase complex subunit 1 (VKORC1) gene and arterial
Genetic Association Studies vascular diseases including PICH (OR 1.53, 95% CI 1.09–2.16; p<0.05)
Apolipoprotein E has been reported.
VKORC1 is implicated in haemostatic processes
Apolipoprotein E (ApoE) is a glycoprotein involved in cholesterol through γ-carboxylation of vitamin-K-dependent proteins. Common
transport and has three isoforms: ε2, ε3 and ε4. Accumulating evidence polymorphisms of VKORC1 gene have also been found to affect
implicates ApoE ε2/ε3/ε4 polymorphism with CAA-related PICH.
The interindividual differences in warfarin sensitivity.
46 EUROPEAN NEUROLOGICAL REVIEW