Biomedical Engineering Reference
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combined into an oligonucleotide ligation assay, has been used for the direct assay
of prevalent mutations in FH. Detection is done by standard multicolor fluores-
cence technology, chemically introduced into oligonucleotides.
Some patients with a family history of hypercholesterolemia have a defect in the
gene for apolipoprotein B, the component of low density lipoprotein that binds the
receptor.10 This ligand defect is called familial defective apoB. One common
mutation of the gene is R3500Q, which occurs in 1/700-1/1,000 people in central
and western Europe. It causes severe hypercholesterolemia and increases the risk
of ischemic heart disease. A simple genetic test for the R3500Q mutation is avail-
able, and some family members of known probands ask to be tested for the gene.
The clinical significance of a positive test may be hard to determine, however,
especially if the individual concerned has a normal cholesterol level.
Gene Mutations Associated with Thrombotic Disorders
A number of thrombotic disorders cause cardiovascular disease as well as stroke
(see the following section on neurological disorders). Venous thrombosis has an
annual incidence of 1/1,000 in the general population and is associated with signifi-
cant morbidity and mortality. Several genetic variants have been identified that are
associated with an increased risk of venous thrombosis, including a recently dis-
covered mutation in the prothrombin gene. Individuals who die suddenly from
pulmonary embolism are not often affected by prothrombin or factor V gene muta-
tions. Factor V Leiden mutation, however, is the most common genetic cause of
idiopathic thrombotic disorders.
Factor V Leiden Mutation
A mutation in the procoagulant protein Factor V (Factor V Leiden) causes it to be
relatively resistant to degradation by activated protein C (APC), resulting in a
thrombotic tendency. The mutation is a guanine-to-adenine substitution at nucle-
otide 1,651 that results in a glutamine-to-arginine substitution at position 506
(R506Q). This is a clinically significant mutation, since it is relatively common
(found in 3-6% of Caucasian subjects) and has been shown to be associated with
venous thrombosis and stroke. There is justification for a rapid method of screening
for this mutation in large populations. THRIMBOGENE, a commercial PCR-based
test for the detection of factor V Leiden mutation, is available from Athena
Diagnostics for identifying a hypercoagulable state in stroke. Although PCR-RFLP
is a standardized assay with relatively reliable performance, the technique is
cumbersome and labor intensive, limiting its general applicability in diagnostic
laboratories. As a result, many laboratories use a functional clotting assay as a
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