Attacking Heart Disease at Its Genetic
Real-time fluorescence detection technology helps biochemist
Jose Ordovas to search for genetic mutations in blood samples from human
volunteers. Color differences on the computer screen indicate the presence or
absence of such mutations.
Suppose we knew all the genes involved in cardiovascular healthwhich
ones contribute to risk, which contribute to protection, and how much each
contributes individually and in combination.
It may sound like a tall order, but that's exactly what researchers here and
abroad are working toward. They want to be able to reduce a person's likelihood
of cardiovascular disease based on his or her genetic profile, as well as on
the individual's age, gender, and lifestyle habits.
A genetic profile would enable individuals to adopt the habits most likely
to reduce riskbecause different genes or gene combinations respond
differently to changes in diet, exercise, smoking, alcohol consumption, or
medications such as cholesterol-lowering drugs. And as more and more
information becomes available, recommendations for change will become more
One of the pioneers in this field is Jose M. Ordovas, a biochemist at the
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in
Boston, Massachusetts. He has identified several of the 40 or so genes so far
known to affect cardiovascular health. He estimates that there may be hundreds
of genes that will ultimately go into a risk-analysis database.
Ordovas explains that four main components under genetic control contribute
to coronary artery disease risk, known as "syndrome x":
- high blood lipidstotal and LDL cholesterol, triglycerides;
- impaired glucose tolerance and diabetes;
- high blood pressure;
- obesity (in the abdomen).
Whether the genes for any of these components are manifest depends on an
individual's habits as well as age, Ordovas says. Moreover, manifestation is
For example, in an obese person, a gene for obesity can trigger a normally
beneficial gene for blood lipids to express high LDL cholesterol and
triglycerides. But if the person stays lean, the beneficial gene could
prevailall other things being equal.
Someday, health professionals will have a fairly complete profile of the
human genes involved in raising or lowering risk, says Ordovas. Children could
be tested early in life so that diet and other lifestyle changes would be
started before damage begins.
No Two Alike
The trouble is, people respond differently to lifestyle changes or to
medications, Ordovas says. For instance, reducing total fat and saturated fat
in the diet doesn't necessarily improve people's blood lipids equallyif
at all. That's due to small differences in their genes.
This genetic factor has produced conflicting results in diet intervention
studies and led to public confusion over the value of changing one's fat
intake. "The appropriateness of one-size-fits-all public health
recommendations is being seriously questioned," says Ordovas.
Tufts University medical technologist Judith McNamara prepares blood serum for
analysis of lipid concentrations.
Since 1983, he and colleagues in the Lipid Metabolism Laboratory have
focused on identifying genes that regulate blood lipids. "We're a little
beyond just finding genes," he says. "Now, we're starting to see
associations between genes and lifestyle."
For example, "people with the APOE4 genotype are prime candidates for
diet therapy. If they follow the standard cholesterol-lowering diet, they can
expect about a 30-percent decrease in LDL cholesterolwhich is what one
can achieve with cholesterol-lowering drugs. But the APOE4 genotype is a poor
responder to the best of these drugs."
On the other hand, notes Ordovas, "people with a specific mutation of
the APOA4 gene have less than half as much improvement in blood lipids from the
cholesterol-lowering diet as those with no mutation." But in a study by
other researchers, he adds, people with a different APOA4 mutation consumed a
high-cholesterol diet without raising their blood cholesterol.
Three years ago, Ordovas enlisted a group of researchers at the University
of Cordoba Medical School in his native Spain to study a gene-diet interaction
with still another of the seven known mutations of the APOA4 gene. Carriers of
this mutation responded to a cholesterol-lowering diet better than noncarriers.
Conversely, they had a greater increase in total and LDL cholesterol when they
returned to a high-fat diet, says Ordovas.
He says a mutation on the APOA1 gene causes a small but similar response
among its carriers. So the Spanish researchers, under Ordovas' guidance, looked
for a gene-gene interaction between these APOA1 and APOA4 mutations. They found
that each gene independently contributed a share to the blood lipid picture:
One gene didn't increase or cancel out the effect of another.
How Apolipoproteins Work
How do these mutations affect blood lipids? The APOE, APOA1, and APOA4 genes
are blueprints for some of the apolipoproteins, or apos, for short. These apos
are like the pilots of ferryboatsHDL and LDLthat move fats and
cholesterol in and out of cells around the body via the bloodstream. Specific
apos pilot specific kinds of ferries into the docks, or receptors, on the cells
so that cargofats and cholesterolcan be loaded or unloaded. Apos
also enable the ferries to exchange cargo in midstream.
Ordovas and coworkers have also found mutations on APOB and APOC3. And they
are identifying mutations on genes that code for enzymes, transport proteins,
and the cell receptors themselves. "We are looking at about 15 genes
involved in lipid metabolism," he says.
The researchers are now focusing on genes that influence how quickly people
clear triglycerides or fats from the blood after eating. One enzyme under
genetic scrutiny is lipoprotein lipase, or LPL, which enables this clearance.
Since we spend most of our time in a fed state, Ordovas says it is important
for researchers to study subjects who are not fasting. One important new
finding from work with fed subjects is that triglyceride-rich lipoproteins
known as chylomicrons and VLDL "contribute to atherosclerosis as much as
LDL," he says.
Ordovas believes this research on genetic factors influencing cardiovascular
health will become more critical as people in developing countries adopt the
higher fat diets and sedentary ways of the West. For many generations, there
has been little selection against genes that predispose to coronary artery
disease in these populations, so high-risk mutations have built up. These genes
didn't express because the people were physically active and ate very low-fat
"Now," says Ordovas, "they are adopting a Western lifestyle,
and we are seeing a huge increase in heart disease."By
Judy McBride, Agricultural
Research Service Information Staff.
This research is part of Human Nutrition Requirements, Food Composition,
and Intake, an ARS National Program described on the World Wide Web at
Jose M. Ordovas is at
the USDA Human Nutrition Research Center
on Aging at Tufts University, 711 Washington St., Boston, MA 02111; phone
(617) 556-3102, fax (617) 556-3103.
"Attacking Heart Disease at Its Genetic Base" was published
in the July 1999 issue of
Agricultural Research magazine.