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Potential Genetic Risk Factors
for Stroke
- Apolipoprotein E4
- Elevated homocysteine levels
- Factor V mutation
Current research in genetic risk factors for
stroke is focusing on the presence of apolipoprotein E4, elevated
homocysteine levels, and factor V mutation.
Apolipoproteins -- the lipid-free, protein components
of a lipoprotein -- are important in the transport of lipids
in plasma. Apolipoprotein E (Apo E) forms part of all
plasma concentration is closely correlated with plasma triglyceride
concentrations. The presence of the apolipoprotein protein-E4
allele has also been associated with an increased risk for
stroke; however, reports are conflicting.
In study designed to identify the possible role
of apolipoprotein E polymorphism in ischemic cerebrovascular
disease, lipoprotein and apolipoprotein profiles were studied
in 100 men with ischemic cerebrovascular disease and 100 healthy,
age-matched controls. [Pedro-Botet J, et al. Stroke.
1992;23:1556.] It was found that apolipoprotein E polymorphism
in the ischemic cerebrovascular patients differed from that
of the control group, with the Apo E4 allele being more prevalent,
suggesting that the Apo 4 allele could be a predisposing genetic
marker for ischemic cerebrovascular disease. However,
in a prospective study of a Finnish non-diabetic cohort, including
1,067 subjects 65 to 74 years old at baseline, there was no
statistically significant difference in the incidence of stroke
at 3.5 years among subjects with no Apo E4 allele, those with
one Apo E4 allele, and those with two Apo E4 alleles, suggesting
that the Apo E4 phenotype is not an important risk factor
for stroke in elderly subjects. [Kuusisto J, et al.
Arterioscler Thromb Vasc Biol. 1995;15:1280.] Research
on the possible role of the Apo E4 allele in stroke is continuing.
Homocysteine is a byproduct of protein metabolism.
It is increased with age, chronic renal failure (CRF), and
estrogen deficiencies and may be implicated in the mechanism
of vascular deficiencies. Plasma levels of the amino
acid homocysteine are determined by a mix of genetic and nutritional
factors. Markedly elevated homocysteine levels, which
were identified 30 years ago as a genetic disease, may cause
life-threatening blood clotting disorders, potentially leading
to strokes and deep vein thromboses in children. In
recent years, researchers have found that moderately elevated
homocysteine levels may occur in people who are heterozygous
for this defect and may also be caused by a deficiency in
forms of vitamin B (folic acid, vitamins B6 and B12).
Prospective studies have shown a linkage between moderately
elevated homocysteine levels and both stroke [Perry IJ, Refsum
H, Morris RW, et al. Prospective study of serum total homocysteine
concentration and risk of stroke in middle-aged British men.
Lancef. 1995;346:1395-8] and myocardial infarction [Chasan-Taber
L, Selhub J, Rosenberg IH, et al. A prospective study of folate
and vitamin B6 and risk of myocardial in US physicians. J
Am Coll Nutr. 1996;15:136-43] in middle-aged and elderly men.
A recent placebo-controlled study found that women, aged 15
to 44 years, who were in the top fourth for homocysteine levels
had a 2.3-fold increased risk of stroke compared to those
in the lower groups [Kittner S, et al. Stroke. 1996;27:16
abs #72]. Among those in whom no cause of stroke could
be determined, the association was even higher (3.4-fold increased
risk). Vitamin B supplements, particularly folic acid, can
lower homocysteine when taken at the recommended dietary allowance
(RDA), but the optimal dosage is unknown, and it remains unclear
whether reducing homocysteine levels will modify stroke risk.
A common point mutation in the gene for coagulation
factor V creates phenotypic resistance to the anticoagulant
effects of activated protein C and predisposes carriers to
venous thrombosis. Some studies have shown a significantly
increased prevalence of the factor V mutation in patients
with stroke or coronary artery disease but other have failed
to show a significant difference [summarized in Press RD.,
et al. Stroke. 1996;27:44]. A recent study [Press et
al] compared the prevalence of this mutation in a group of
161 elderly patients with acute ischemic stroke, 116 elderly
patients with stroke risk factors without acute stroke, 54
elderly control subjects, and 287 young control individuals.
The results indicated that the factor V mutation is not a
significant genetic risk factor for ischemic stroke in the
elderly. However, since the prevalence of this mutation
was significantly higher in the two younger control groups
than in the elderly stroke patients, the authors suggested
that a complete hypercoagulability workup (including a factor
V mutation analysis) may be clinically justified in younger
patients, in those with significant atherosclerosis, or in
those with a significant family history of venous thrombosis.
Such limited screening might identify those patients at highest
risk who might benefit most from prophylactic or therapeutic
anticoagulants.
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Stroke Education
