There is no question that coronary artery disease (CAD) runs
in families. We know that first-degree relatives of people who develop CAD at an early age are at a much higher
risk for developing CAD than the general population. By better understanding the genetics of this disease, you can more accurately
assess your risk and be on the lookout for early warning signs.
Researchers
have identified more than 250 genes that may play a role in CAD. Although researchers are a long way from confirming whether even half of those genes are
actually involved, we do know that CAD often results from the blended effects of multiple genes. These so-called polygenic
effects mean that the genetics of CAD are extremely complicated, with many different genes influencing a person's risk. In
most cases, CAD is not inherited in a clearly dominant or recessive manner. Instead, a person may have mutations in some genes that increase risk and mutations in other genes that decrease risk. On average, a person's risk level
is approximately midway between those of the parents.
Rather
than discuss all 250 genes that have been implicated, it makes sense to focus on several of the best-understood genes. As
you examine the following information, keep in mind that this field is rapidly changing. The roles of many of these genes
have not yet been fully defined.
For recent
news about genes that are implicated in CAD, see Related News below.
=====
Genetic study questions
HDL levels and the risk of MI
Boston, MA - Therapies that boost HDL-cholesterol levels are currently viewed as a potential treatment to close
down the residual risk of aggressively treated patients, but data from a new study throw cold water on the putative benefits
of raising HDL-cholesterol levels to reduce the risk of MI [1].
Investigators report that a genetic variant that substantially raises HDL-cholesterol levels did not alter the
risk of MI, whereas genetic polymorphisms related to plasma LDL-cholesterol were consistently associated with an increased
risk of MI.
"These results challenge several established views about plasma HDL cholesterol," write Dr Benjamin
Voight(University of Pennsylvania, Philadelphia) and colleagues in a report published online May 16, 2012 in the Lancet.
"First, these data question the concept that raising plasma HDL cholesterol should uniformly translate into reduction in risk
of myocardial infarction. . . . Second, these findings emphasize the potential limitation of plasma HDL
cholesterol as a surrogate measure for risk of myocardial infarction in intervention trials."
In an editorial accompanying
the study [2], Drs Seamus Harrison, Michael Holmes, and Steve Humphries(University College London,
UK) echo the conclusions of the researchers, stating that "genetically raised HDL-cholesterol concentrations do not seem to
reduce risk of coronary heart disease—an observation that calls into question whether raising HDL cholesterol therapeutically
would translate into the expected clinical benefit."
The genetic data emerge after a couple of high-profile failures
with drugs, as well as extended-release niacin, which showed no benefit in terms of hard clinical events despite
substantial increases in HDL-cholesterol levels.
Earlier this month, Roche stopped the phase 3 dal-OUTCOMES trial of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib after interim analysis
of the study showed the HDL-cholesterol-boosting drug did not reduce cardiovascular adverse events. The AIM-HIGH study, with niacin given on top of statin therapy, showed the vitamin significantly increased HDL-cholesterol levels
but failed to reduce the composite end point of coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization
for acute coronary syndrome or symptom-driven coronary or cerebral revascularization. And of course, torcetrapib, another CETP inhibitor, was stopped in late 2006 when investigators discovered the drug increased the risk of death and
cardiovascular events.
HDL and MI: It's a complicated relationship
In the present study,
the researchers performed two Mendelian analyses. With the first, they tested the association with a single nucleotide polymorphism
(SNP) in the endothelial lipase gene (LIPG Asn 396Ser) in 95 407 healthy controls and 20 913 patients
who had an MI.
Carriers of the LIPG Asn 396Ser allele, which occurred in 2.6% of the study cohort,
had HDL-cholesterol levels approximately 5.5 mg/dL (0.14 mmol/L) higher than those without the allele but similar levels of
other lipids. Despite the increase in HDL cholesterol, carriers of the LIPG Asn 396Ser allele did not have
a significantly decreased risk of MI (odds ratio 0.99; 95% CI 0.88-1.11). Similarly, in an analysis of six prospective cohort
studies alone, which included 46 535 controls and 4228 MI patients, as well as a separate analysis of case-control studies,
there was no significant association between the LIPG Asn 396Ser allele and the risk of MI.
On the basis of the
association between the LIPG Asn 396Ser allele and HDL cholesterol, the increase in HDL should have translated
into a 13% decreased risk of MI.
The researchers also constructed a genetic score by combining common SNPs that had
statistical evidence at genomewide levels of significance for plasma LDL- and HDL-cholesterol levels. The genetic score for
LDL and HDL cholesterol included 13 and 14 SNPs, respectively. In the Mendelian randomized analysis, each standard-deviation
(SD) increase in LDL cholesterol due to the genetic score significantly increased the risk of MI (OR 2.13; 95% CI 1.69-2.69).
In contrast, each 1-SD increase in HDL cholesterol due to the genetic score did not decrease the risk of MI.
Based on these data,
"interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a
corresponding benefit with respect to risk of myocardial infarction," conclude Voight and colleagues.
Trials with drugs
that raise HDL cholesterol remain ongoing. More data on the use of niacin will come from the 24 000-patient HPS2-THRIVE study, while other CETP inhibitors, evacetrapib (Lilly, Indianapolis, Indiana) and anacetrapib (Merck, Whitehouse Station, NJ), are still in development.
July 18, 2007 -- The odds of getting heart disease may lie, in part, in six genes identified today by European researchers.
Variations in those six genes appear to be more common in people who have heart attacks or heart disease before age 66, according to the scientists.
But that doesn't mean that people with
those gene variations are doomed to develop heart disease or suffer a heart attack at a young age.
"Even
if a person carries one or more of these risk variants, they can still do a lot to reduce their risk by adopting a healthy
lifestyle, not smoking, and, if they have high blood pressure or raised cholesterol levels, to have these treated," Nilesh Samani, FMedSci, says in a news release.
Samani works at England's
University of Leicester and was involved in the heart disease gene study, which appears in today's online edition of The
New England Journal of Medicine.
Heart Disease Genetics
Heart disease is the leading
cause of death for U.S. men and women.
Heart disease risk may be handed down from generation to generation
through genes. But genetics are only part of the story.
For instance, it's well known that smoking makes heart disease
(and many other health problems) more likely. So do obesity and inactive lifestyles.
Samani's study focuses
only on genetics -- not whether people were couch potatoes, how often they exercised, whether they ate leafy green vegetables
every day or once a decade, or had any other habits that might sway their heart health.
The key question: Were
the genetic cards stacked against certain people?
6 Heart Disease Genes
First,
the researchers scrolled through the DNA of nearly 2,000 Europeans who had a heart attack or other forms of heart disease
before age 66.
For comparison, they also studied the genes of some 2,900 Europeans of the same age who had no history
of heart trouble.
The people with heart disease were more likely than those with healthy hearts to have certain gene
variations.
Samani's checked their findings in 875 Germans who survived a heart attack before age 60 and more
than 1,600 Germans with no heart problems.
The scientists combined all their data and came up with six
genetic variants that were linked to heart attacks or heart disease.
Those variants are in or
near the MTHFD1L, PSRC1, MIA3, SMAD3, CDKN2A/CDKN2B, and CXCL12 genes.
Gene Role in Heart Disease?
The
researchers don't yet know exactly how those genes affect heart disease risk.
But a journal editorial notes
that the gene variant that was most strongly linked to heart disease is associated with genes that govern cell death.
However, the editorial also points out that all of the participants in the gene study were white Europeans.
More diverse studies are needed to see if the findings apply to people of other racial and ethnic backgrounds, notes
editorialist Anthony Rosenzweig, MD.
Rosenzweig works in the cardiovascular division of Boston's Beth
Israel Deaconess Medical Center and Harvard Stem Cell Institute.
Eating Raw Fruits And Vegetables May Alter Heart Disease Gene
It's thought that genetic factors are being unmodifiable factors.
Genes can not be changed. Lifestyle modification can make the gene behave differently.
Chromosome 9p21, one of the most potent genes associated with heart disease can be turned off by eating
fresh fruits and vegetables
".......t diets high in fresh fruits and vegetables actually mitigated the effect
of 9p21, regardless of the individual’s genetic disposition. Individuals with the high risk genotype could reduce their
risk factor to the same level as those with the low risk genotype when following a "prudent diet", one composed of mainly
raw fruits, berries, and vegetables".
===
According to a new study out of McMaster and McGill Universities led by an international team of scientists, eating fresh fruits and vegetables can help turn off one of the most potent
genetic associations with heart disease, a gene more affectionately known in the medical world as Chromosome 9p21.
Through one of the largest gene-diet interaction studies ever conducted on cardiovascular disease, the researchers
analyzed more than 27,000 people from various ethnicities around the world and the effects their diet had on the 9p21 gene.
"We often think of genetic factors as being unmodifiable factors," Dr. Sonia Anand, a joint principal investigator
of the study and professor of medicine and epidemiology at the university, told ABC News. "But lifestyle factors can actually change the genes."
The results of the global retrospective
supported the "five a day" recommendation, finding that diets high in fresh fruits and vegetables actually mitigated the effect
of 9p21, regardless of the individual’s genetic disposition. Individuals with the high risk genotype could reduce their
risk factor to the same level as those with the low risk genotype when following a "prudent diet", one composed of mainly
raw fruits, berries, and vegetables.
"What this study seems to imply is that you shouldn’t throw
in the towel if you have a family history or are at risk for heart disease because healthy living with a healthy diet, in
addition to other lifestyle changes such as exercise and maintaining a healthy body weight, can take away from the risk that
genes give you,” Beth Abramson, a cardiologist at St. Michael’s Hospital in Toronto who was not involved in the
research, told The Canadian Press.
This is all welcomed news as in the US alone, coronary heart disease is the leading cause of death, with stroke, another
cardiovascular disease, ranking third on the list of killers. Regardless if you have the high risk gene or not, previous research shows that every additional serving of fruits or vegetables can bring about a four percent decrease in the rate of heart
disease related deaths.
"Future research is necessary to understand the mechanism of this interaction, which will shed light on the underlying metabolic
processes that the 9p21 gene is involved in," the study's lead author, Dr. Ron Do, notes in the joint university press release.
Meanwhile, Anand advises consumption
of "more than five fruits or vegetables" daily to promote good health.
So in the interim, consider making that "apple a day" an additional serving,
rather than your one and only.
==================
Genetics of Cardiovascular Disease
Dianna M. Milewicz, MD, PhD; Christine E. Seidman, MD.Circulation. 2000;102:IV-103-IV-111
A gene that almost guarantees serious heart disease in middle age is carried by an estimated 60 million people
around the world, a team of scientists has found.
The
one in 100 who inherit the mutation usually show few, if any, symptoms before their 40s, but become ill as they get older,
with many later dying from heart failure.
The discovery
marks the strongest link yet that scientists have made between a person's genetic make-up and their risk of succumbing to
heart disease.
The risk of being born with
the abnormal gene is substantially higher in people who can trace their ancestry back to the Indian subcontinent, where one
in 25 inherit the mutation. "The bad news is that many of these mutation carriers have no warning that they are in danger,"
said Perundurai Dhandapany at Madurai Kamaraj University, a co-author of the study published in Nature Genetics.
The mutation was originally identified
in two Indian families with heart disease five years ago, but only after studying almost 1,500 people from different regions
of India did the importance of the abnormal gene become clear.
Researchers compared the genetic make-up of 800 patients with heart disease and 699 healthy volunteers. They found those
with heart problems often carried the mutation, in which 25 letters of genetic code needed to make heart muscle proteins are
missing.
"The mutation leads to the formation of
an abnormal protein. Young people can degrade the abnormal protein and remain healthy, but as they get older it builds up
and eventually results in the symptoms we see," said Kumarasamy Thangaraj at the Centre for Cellular and Molecular Biology in Hyderabad, who led the study.
Chris Tyler-Smith,
a co-author at the Sanger Institute near Cambridge, said the mutation probably arose in India around 30,000 years ago and
was able to spread because it usually only affects people after they have had children.
With genetic screening it would be possible to identify people with the gene at an early age, though in the near
term, doctors could only advise them to improve their lifestyle to reduce their risk of heart disease. In the longer term,
scientists hope to develop a treatment using a drug to boost the body's ability to break down the abnormal heart protein.
"This is a genetic finding of great importance," said Sir Mark
Walport, director of the Wellcome Trust. "Heart disease is one of the world's leading killers, but now that researchers have
identified this common mutation, carried by one in 25 people of Indian origin, we have hope of reducing the burden that the
disease causes. This research should lead to better screening to identify those at risk and may ultimately allow the development
of new treatments."
===========
A Prospective Evaluation of an Angiotensin-Converting–Enzyme
Gene Polymorphism and the Risk of Ischemic Heart Disease
Klaus Lindpaintner, M.D., Marc A.
Pfeffer, M.D., Ph.D., Reinhold Kreutz, M.D., Meir J. Stampfer, M.D., Dr.P.H., Francine Grodstein, Sc.D., Fran LaMotte, B.S.,
Julie Buring, Sc.D., and Charles H. Hennekens, M.D., Dr.P.H.
