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Genetic Susceptibility to Primary Intracerebral Haemorrhage
Interleukin-6 Gene promoting amyloid plaque formation. The TT genotype of ACT A/T signal
In a large-scale association study, 282 Japanese patients with PICH and peptide polymorphism was associated with PICH in Spanish patients (OR
2,010 controls were genotyped for 202 polymorphisms of 152 genes 2.80), especially those with normal blood pressure (OR 3.40).
53
By
that were implicated in vascular biology, platelet function, leukocyte contrast, a study from China reported a more robust association in
biology, coagulation processes, regulation of the circulation, blood hypertensive patients.
54
However, these associations were not replicated
pressure or endocrine function and various metabolic factors, as well in a study from Poland
55
and in a group of 147 Greek patients from our
as lipid, glucose and homocystein metabolism. It was found that the department.
56
In our group we observed only a marginal association in
C allele of the interleukin-6 (IL-6) gene -572G/C polymorphism the non-hypertensive group (p=0.05). It is possible that in non-
hypertensive patients the absence of hypertension unmasks the
relatively minor effects of ACT A/T signal peptide polymorphism on
Primary intracerebral haemorrhage
the cerebral vasculature, making it more susceptible to haemorrhage.
is a complex multifactorial disorder
Lipoprotein a Gene
that probably results from an interaction
Elevated lipoprotein a (Lp(a)) levels have been associated with increased
between various environmental
risk of cardiovascular diseases, possibly by being implicated in
atherosclerotic arterial damage. In a large multicentre study in a Chinese
factors and the genetic background
population, low numbers of TTTTA repeats (PNTR polymorphisms) of the
of the patient.
Lp(a) gene were found in patients with PICH.
57
Apolipoprotein H Gene
increased the risk of PICH (OR 1.57, 95% CI 1.21–2.07; p<0.001). It was Apolipoprotein H (ApoH) has been implicated in several physiological
suggested that IL-6 may damage the vascular wall through induction of pathways including lipid metabolism, coagulation and increased
matrix metalloproteinases, which degrade the extracellular matrix blood pressure. In a study in a Chinese population it was found that
around blood vessels and thus weaken the vascular wall.
48
However, the Ser88Asn (G341A) polymorphism was associated with increased
recently, in a small group of patients IL-6 -174G/C gene polymorphism risk of PICH.
58
was not found to be an independent risk factor for PICH.
49
Platelet Glycoproteins
Engoglin Gene Glycoproteins Ia, IbA and IIIa are platelet surface receptors for
Endoglin is a glycoprotein in the surface of endothelial cells that interacts fibrinogen, von Willebrand factor and collagen, playing an important role
with transforming growth factor-β. Endoglin is important for vascular in platelet adhesion and aggregation. However, genetic polymorphisms
development and structural integrity. Variable mutations in the endoglin of these factors were not found to increase the risk of PICH.
59
gene were found to cause hereditary haemorrhagic telangiectasia. A
homozygous 6bp insertion in the endoglin gene was found in 8.7% of
PICH patients compared with 2% of controls (OR 4.76, 95% CI 1.28–21.6;
Implementation of genome-wide scans
p=0.012).
50
The same polymorphism was also associated with increased
may provide substantial benefits,
frequency of intracranial aneurysms.
including the development of genetic
Angiotensin-converting Enzyme Gene
markers for determination of specific
Angiotensin-converting enzyme (ACE) plays an important role in
regulating both the production of angiotensin II and the degradation
molecular profiles in individuals and
of bradykinin at the endothelial surface. Angiotensin II, which is the
assessment of disease risk.
main active product of the renin–angiotensin system, has been linked
to vascular remodelling, inflammation and endothelial dysfunction. It
was reported that the DD genotype of ACE insertion/deletion (I/D) PAF-H Gene
polymorphism in intron 16 was over-represented in Polish patients Platelet-activating factor acetylhydrolase (PAF-H) is implicated in
with non-lobar PICH (OR 2.13, 95% CI 1.10–4.14; p=0.02). However, thrombosis. A Val2793Phe substitution in the PAF-H gene has been
after excluding the individuals who were receiving ACE inhibitors and associated with ischaemic stroke, possibly through increased
adjusting for other variables, the association was no longer thrombotic processes. The same mutation was also found to be a risk
statistically significant.
51
In a previous study, the distribution of ACE factor for PICH.
60
genotypes and alleles was the same among the controls and
patients.
52
It was shown that ACE I/D polymorphism only partially Factor XIII Gene
determines the variation in plasma ACE levels, and it is uncertain Blood coagulation factor XIII plays an important role in clot
whether it represents a functional polymorphism; this may explain the stabilisation by cross-linking fibrin chains. A point mutation in codon
inconsistency between the two studies. 34 (Val34Leu) of XIII gene was known to be protective against
thrombotic diseases including myocardial infarction and ischaemic
Alpha-1 Antichymotrypsin Gene stroke. However, a potential association of Val34Leu and PICH was
Alpha-1 antichymotrypsin (ACT) is an acute-phase protein member of reported.
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The authors suggested that the Leu34 allele might cause
the serine proteinase inhibitors that has been implicated in vascular the formation of weaker fibrin structures that predispose to PICH.
pathology. ACT has anti-inflammatory properties as it strongly inhibits Subsequently, this polymorphism was extensively investigated in
neutrophil cathepsin G, but it is also known to interact with Aβ peptide, various populations but with contradictory results.
62–66
EUROPEAN NEUROLOGICAL REVIEW 47
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