plasminogen activator inhibitor (PAI-1) 4G/5g
polymorphism
The
Coagulation and Molecular Immunodiagnostics Laboratory
of ITxM Diagnostics is pleased to offer a genetic assay
for the detection of PAI-1 4G/5G Polymorphism
BACKGROUND
The
type 1 plasminogen activator inhibitor (PAI-1) is a
primary regulator of the fibrinolytic system in vivo.
PAI-1 binds to tissue plasminogen activator and inhibits
plasminogen activation, which decreases fibrinolysis. A
single guanosine insertion/deletion (4G or 5G) 675 base
pairs from the start site of the genes promoter region
affects an individual’s predisposition for thrombosis.
Studies have shown a correlation between PAI-1 levels in
plasma and the 4G/5G polymorphism. Subjects with the
4G/4G genotype have plasma PAI-1 concentrations that are
25% higher than those with the 5G/5G genotype.
Increased PAI activity may be associated with increased
risk for venous thrombosis and myocardial infarction.
The prevalence of the 4G/4G genotype in the normal
population is 26%.
METHODS
Lymphocytes are processed to extract DNA. Third Wave
Technologies’ Invader assay is used to genotype the
target DNA. Briefly, two specific oligonucleotide
probes and controls hybridize in tandem to a specific
region of the gene encoding the mutation site. Cleavase
III enzyme cleaves at a specific invasive structure
generated within the probe oligonucleotides creating
products. These sequential cleavage reactions produce
1-10 million fluorescein labeled products per target
sequence hour. This results in the accumulation of a
signal molecule only when the specific target DNA or
control sequence is present. A fluorescent multiwell
plate reader is used to quantitate signal amplification
for interpretation of genotype. Homozygosity for the 4G
polymorphism is associated with increased thrombotic
risk.
CLINICAL SIGNIFICANCE
In
population studies, a family history of ischemic
coronary events is a major predictor of coronary artery
disease (1). In addition, several twin studies have
shown a strong genetic component in the pathogenesis of
cardiovascular ischemia (2). These findings support the
hypothesis that genetic factors play a significant role
in MI and vascular risk factors (3). Impaired
fibrinolysis is related to raised plasma levels of PAI
and has been documented in subjects who
develop MI.
Recently increased PAI plasma levels have been shown to
be related to a single base pair guanine
deletion/insertion (4G/5G) polymorphism (4). Subjects
with the 4G homozygous genotype have plasma PAI
concentrations that are 25% higher than those with the
5G homozygous genotype. There is substantial evidence
reported in the literature to support that carrier
status of the 4G polymorphism with increased PAI levels
is an independent risk factor for coronary events. It
is recommended that the PAI 4G/5G genetic assay be used
in the following situations:
Ø
Patients presenting with family histories of early heart
disease and stroke
Ø
Patients with coronary heart disease
Ø
Patients undergoing vascular surgery
Ø
Pregnant women with past complications during pregnancy.
Ø
Select cases of patients with family history of venous
thrombosis
SPECIMEN REQUIREMENTS
In
order to assure the accuracy of our test results, the
PAI-1 4G/5G polymorphism assay must be performed on
whole blood .
1.
Blood must be collected in one (1) yellow top tube (ACD).
DO NOT centrifuge the specimen and DO NOT separate
plasma.
2.
Ship sample at room temperature.
3.
Specimen must be received within 72 hours of collection.
4.
We request that a completed
Genetic Consent Form accompany the specimen.
TEST INFORMATION
The
PAI-1 4G/5G Polymorphism testing fee is $180.25.
TEST CODE: 5620 CPT CODES: 83891 83892x2 83896x2 83903x2
83912
This test was developed and its performance
characteristics determined by ITxM Diagnostics. It has
not been cleared or approved by the U.S. Food and Drug
Administration. This test is used for clinical purposes
and should not be regarded as investigational or for
research use. This laboratory is certified under the
Clinical Laboratory Improvement Amendments of 1988 (CLIA)
as qualified to perform high complexity clinical testing.
FOR FURTHER INFORMATION
CONTACT 412-209-7270 OR 1-800-967-9672
REFERENCES
-
Margaglione, M.; Cappucci, G., Colaizzo, D., Giuliani,
N., Vecchione, G., Grandone, E., Pennelli, O.; DiMinno,
G., The PAI-1 Gene Locus 4G/5G Polymorphism Is
Associated with a Family History of Coronary Artery
Disease. Arterios.Thromb. Biol, 18: 152-156, 1998.
-
Glueck, G.J., Phillips, H., Cemaron, D., et.al., and
The 4G/4G polymorphism of the hypofibrinolytic
plasminogen activator inhibitor type 1 gene: an
independent risk factor for serious pregnancy
complications. Metabolism 49: 845-852, 2000.
-
Anvari, A., Schuster, E., Gottsauner-Wolf, M., et.al.,
PAI-1 4G/5G polymorphism and sudden cardiac death in
patients with coronary artery disease. Thromb. Res.
103: 103-107, 2001.
4. Francis, C.F. Plasminogen Activator Inhibitor-1
Levels and Polymorphisms. Association with Venous
Thromboembolism. Arch. Pathol Lab Med. 126: 1401-1404,
2002
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