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ABSTRACT:
Summary:
Scientists at Berkeley Lab have found a new apolipoprotein
gene that greatly influences both human and mouse triglyceride
and VLDL levels, both of which are a major risk factor for
cardiovascular disease.
The
human gene, which Edward Rubin and Len Pennacchio have named
ApoAV, was discovered near the ApoAI/CIII/AIV cluster of apolipoprotein
genes on human chromosome 11. This region is known to have
a major influence on plasma lipid profiles and, consequently,
atherosclerosis susceptibility. It is also well known that
mutations in DNA sequences within this region can contribute
to severely elevated triglyceride levels, although such sequence
changes are extremely rare. Rubin and Pennacchio have collected
strong data supporting a major effect of human ApoAV variants
in determining population-based increases in plasma triglyceride
levels. Their further studies in mice provided consistent
results with the clinical findings.
Research:
The human ApoAV gene was introduced into a line of mice through
standard transgenic technology and engineered to over-express
itself. In addition, using gene knockout technology, Rubin
and Pennacchio also engineered mice that lacked ApoAV. Comparing
the two groups revealed a dramatic contrast.
“Mice with increased expression of human ApoAV showed
a 70-percent decrease in plasma triglyceride concentrations
while mice lacking ApoAV (the ApoAV knockouts) showed a 400-percent
increase,” says Pennacchio. “The results from the
two studies strongly supported one another.”
Most
importantly, when they extended their studies to the human
population they made a profound discovery. Human ApoAV polymorphisms
were found to be strongly associated with triglycerides in
the general population, consistent with their findings in
mouse studies. These ApoAV variants are found in 10% of human
chromosomes and are associated with an approximately 30% increase
in plasma triglycerides. Furthermore, Rubin and Pennacchio
were able to replicate their initial result, which supports
the finding that about one in five individuals in the population
has increased triglycerides due to variation in the human
ApoAV gene.
Clinical and Pharmaceutical Applications: Using the
ApoAV gene for early detection, diagnosis, and treatment of
genetically induced cardiovascular disease may have a profound
clinical impact. The possibilities for application are vast.
Drug therapies can be designed to raise the levels of this
protein in human patients with high VLDL levels, thus reducing
VLDL and triglyceride levels and reducing the risk of cardiovascular
disease. The protein can be used in screening to identify
gene abnormalities that lead to cardiovascular disease. Direct
delivery of the ApoAV protein or a mimicking molecule in someone
with high VLDL levels may reduce those levels.
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