High-density lipoprotein, or HDL, has long been thought of as good cholesterol due to its ability to rid the body of bad cholesterol, reduce the risk of heart disease, transport bad cholesterol to the liver where it can be processed, and keep the inner walls of the blood vessels free of clot.
Do you want to know why? The article below is is curled from Science Daily. Com
''A new paper published
online in The Lancet challenges the
assumption that raising a person's HDL --
the so-called "good cholesterol" -- will
necessarily lower the risk of a heart
attack. The new research underscores
the value of using genetic approaches to
test biological hypotheses about human
disease prior to developing specific
drugs. A team led by researchers from
the Broad Institute and Massachusetts
General Hospital (MGH) explored
naturally occurring genetic variations in
humans to test the connection between
HDL levels and heart attack. By
studying the genes of roughly 170,000
individuals, the team discovered that,
when examined together, the 15 HDL-
raising variants they tested do not
reduce the risk of heart attack.
"It's been assumed that
if a patient, or group of
patients, did something
to cause their HDL
levels to go up, then
you can safely assume
that their risk of heart
attack will go down,"
said senior author
Sekar Kathiresan,
director of preventive
cardiology at MGH,
associate professor of
medicine at Harvard
Medical School, and an
associate member of
the Broad Institute. "This work fundamentally
questions that."
Each of the variants Kathiresan and his
colleagues studied reflects potentially distinct
ways the body might raise HDL. The findings
raise significant questions about whether
developing drugs against the genes explored in
this study, which involves an international
team of investigators to bring together patient
samples, will prove effective in lowering heart
attack risk across the population.
"Our study highlights the value of human
genetic information in understanding disease
biology prior to developing and testing drugs
in the clinic," said co-author David Altshuler,
director of the Program in Medical and
Population Genetics at the Broad Institute and
a Harvard Medical School professor at MGH.
"This kind of research is not about
personalized prediction -- rather, it's about
testing mechanisms and therapeutic
hypotheses before drug discovery."
In the blood, cholesterol is carried by particles
called lipoproteins, which come in different
sizes and densities. These include HDL, or
high-density lipoprotein, and LDL, or low-
density lipoprotein. There is a well-studied
connection between elevated LDL, often called
the "bad cholesterol," and heart attack.
Decades of research, including studies of
genetic disorders in humans and the discovery
of the LDL receptor and its role in cholesterol
regulation, paved the way for the development
of life-saving drugs known as statins. This
work showed beyond any reasonable doubt
that many different methods of reducing a
person's LDL levels lower the risk of heart
disease.
Large-scale studies of genetic variation tied to
LDL have been revealing, but the data on HDL
are not so clear. More than 30 years ago,
human epidemiological studies first revealed
an association between HDL and risk for heart
attack: the higher the levels, the lower the
risk. Experiments in cells and mice further
support the idea and suggest that HDL is
protective because it may remove cholesterol
from the sites where it can do damage.
However, it has been difficult for researchers
to prove conclusively that raising HDL levels is
beneficial, primarily for two reasons. First,
studies of human genetic diseases where
individuals have very low HDL levels have not
yielded definitive answers as to the impact on
heart attack. And second, because there are
currently no drugs that specifically elevate
HDL levels, it has been difficult to prove in
humans that such an intervention will lower
heart attack risk.
"There are many biomarkers measurable in the
blood that track with disease but only a very
small number are actually causal and directly
participate," said first author Benjamin
Voight, who since completing this work has
left the Broad and MGH for a position as an
assistant professor at University of
Pennsylvania. "The reason you want to
distinguish between causal and non-causal
biomarkers is because of the implications for
therapy."
To investigate, Kathiresan teamed up with
colleagues from MGH, the Broad Institute, and
beyond, including Voight and co-first author
Gina Peloso. Together, the researchers looked
to the human genome for help.
Individuals typically carry two copies of each
gene in the genome; which copy a child will
inherit from each parent is essentially a
random decision, like flipping a coin. This
phenomenon, sometimes called "Mendelian
randomization," provides a powerful means of
testing connections between genes, biomarkers,
and disease -- similar to the way that
randomized controlled clinical trials can
evaluate the effectiveness of new drugs.
Using this technique, researchers study two
groups of people -- those who carry a particular
gene variant, and those who do not. When
sufficiently large groups are studied, both
groups should be similar in every factor,
except for the specific gene variant or
biomarker of interest, allowing researchers to
home in on whether the biomarker actually
causes a particular trait or condition. By
harnessing this method, Kathiresan and his
team tested whether certain genetic variants
that can dial up a person's HDL levels impact
the chances of developing heart attack.
What they found was surprising. Individuals
who carried a particular variation in a gene
called endothelial lipase had HDL levels that
were elevated about 6mg/dl, or 10% -- a change
expected to decrease heart attack risk by
about 13%. However, these individuals showed
no difference in their risk of heart disease
compared to people without the variant.
Similarly, the researchers identified a panel
composed of not just one but 14 different HDL-
raising variants. They devised a scoring system
based on the total number of copies of the
gene variants a person carries -- ranging from
0 to 28 -- and then asked whether that score
relates to the risk of heart attack. Here also
they uncovered no association.
Kathiresan emphasizes that these results do
not diminish the value of HDL levels as a
predictor -- a so-called biomarker -- that can
help estimate the likelihood of a person going
on to develop heart attack. "We know that
HDL is a great biomarker -- it's quite useful in
identifying individuals at higher risk of
having a heart attack in the future," said
Kathiresan. "But we have shown that you
cannot assume that raising HDL by any
mechanism will help patients. Perhaps other
mechanisms exist that can lower risk, but we
will need to keep searching for them."
"It takes a decade or more, and costs up to
hundreds of millions of dollars, to discover a
drug and carry out clinical trials. And yet, the
vast majority of such clinical trials fail due
to lack of efficacy or toxicities," said
Altshuler. "Human genetics offers a valuable
approach to evaluating the underlying
therapeutic hypothesis prior to spending so
much time and money on drug discovery,
hopefully allowing the industry to focus
resources on hypotheses that are most likely to
prove safe and effective in patients."
Other study contributors from the Broad
Institute include Christopher Newton-Cheh,
Kiran Musunuru, James Pirruccello, Paul de
Bakker, Mark Daly, Candace Guiducci, Noel
Burtt, Aarti Surti, Elena Gonzalez, Shaun
Purcell, and Stacey Gabriel.
This work was funded by the National
Institutes of Health, The Wellcome Trust,
European Union, British Heart Foundation and
the German Federal Ministry of Education and
Research.''
No comments:
Post a Comment