A new report in the Journal of the American Medical Association adds to the mounting evidence that genetic variations impact the efficacy of clopidogrel (Plavix®), a drug used to prevent blood clots in people who have had a heart attack or stroke and also those with peripheral artery disease and unstable angina.

Previous research has shown that certain variations in the CYP2C19 gene prevent the body from converting clopidogrel into its active form. That reduces the amount of anti-clotting effect people get from the medication, increasing their risk for heart attacks, strokes and death from cardiovascular causes.

(23ndMe customers can learn how their data fits in with this research in a previous Spittoon post or in the Clopidogrel Efficacy Drug Response Report.)

The researchers, led by Alan Shuldiner of the University of Maryland School of Medicine, determined that BMI, lipid levels and age account for about 10% of the variation in clopidogrel’s ability to prevent blood clotting. Variation in the CYP2C19 gene accounted for another 12%, meaning that other factors, probably both genetic and non-genetic, are also at work.

For patients whose genetics may reduce the benefits of clopidogrel treatment, there are other options. Prasugrel (Effient®) was recently approved by the FDA and appears not to be affected by the same variations that impact clopidogrel efficacy, although there are some concerns about bleeding caused by this drug.  Several other drugs (ticagrelor, cangrelor, elinogrel) that could be used for clotting reduction in place of clopidogrel are currently in clinical trials.

Clinical trials have not yet been conducted to show if identifying people with variants of the CYP2C19 before prescribing clopidogrel actually improves health outcomes.  If such studies do show a benefit and this type of testing becomes routine, people with these variants might be steered away from clopidogrel by their doctors, which would seem to be a boon for the makers of newer medications.

But in an editorial accompanying the study in JAMA, Deepak Bhatt suggests that testing for these variations would also allow physicians to know for whom clopidogrel will work (probably). This would be an important piece of information considering that the patent on clopidogrel is set to expire in 2011, so cheaper generic forms of the drug will be available then.

“Although such testing currently is expensive, the cost will decrease and hopefully will coincide with supportive data.  Furthermore, if such testing allowed use of a less expensive generic anitplatelet drug, the test might essentially pay for itself,” he writes.

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It has been known for decades that having the gum disease periodontitis increases a person’s risk for heart attack (free registration required), stroke and other forms of cardiovascular disease. Research suggests that the link is due to inflammation in the gums causing an immune reaction throughout the entire body. That can increase blood pressure and encourage the accumulation of atherosclerotic plaques in the arteries.

Now researchers have drawn a genetic link between periodontitis and heart disease as well. It turns out that variations in a region of chromosome 9 that have already been associated with heart disease also influence a person’s chances of developing periodontitis.

The specific genetic marker identified by the study is not part of the 23andMe Personal Genome Service. But another marker that has also been linked to heart disease and lies in the same chromosomal neighborhood is described in the Heart Attack research report.

Arne Schäfer of the Institute for Clinical Molecular Biology in Kiel, Germany presented the research in Vienna, Austria, last week at the annual meeting of the European Society of Human Genetics. He and his colleagues found that people with a marker for increased cardiovascular risk in a stretch of DNA known as 9p21 were more likely to have gum disease as well.

The high-risk version of the marker increased a person’s chances of having generalized aggressive periodontitis by 1.99 times, and localized aggressive periodontitis 1.72 times. Aggressive periodontitis generally strikes early in life and progresses rapidly, leading to tooth loss as early as age 20.

The 9p21 region of chromosome 9 contains several genes involved in suppressing the proliferation of cells. In a recent PLoS Genetics paper the researchers suggest that the variation they studied somehow affects the function of one of these genes.

Rather than superceding previous findings linking the effects of periodontal inflammation itself on heart disease, the researchers said, their study provides valuable additional information that could help unravel the connection between the two conditions.

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For the millions of Americans who suffer from migraines, the risk of throbbing pain that can last for days is plenty to worry about.  But studies have shown that having a propensity for these severe and sometimes disabling headaches can also increase the risk for cardiovascular events such as stroke and heart attack.

In new report published this week in Neurology, researchers using data from the Women’s Health Study suggest that only those women with a specific genetic variation and whose migraines include aura, a type of visual disturbance characterized by flashing lights and patterns, are at increased risk for cardiovascular disease (CVD).

Previous studies have attempted to link both migraines and CVD with a variation referred to as the D/I polymorphism in ACE, a gene that encodes a blood vessel-constricting protein.  Drugs that inhibit the ACE protein are used to treat migraines and CVD.

In a study that included 25,000 women with European ancestry, about 3,200 of whom had migraines, Schürks et al. found no association of the D/I polymorphism with the headaches. Over 12 years of follow-up, there were 625 cardiovascular events (mainly strokes and heart attacks) in the group, but again, no association with the D/I polymorphism.

When the researchers took genetics out of the equation, they found that a woman with a history of any type of migraine was about 30% more likely to have CVD.  But when they added genetics back in and also divided the migraneurs (people who get migraines) up based on the presence or absence of aura, they found that only those women who had migraine with aura and also had the DD or DI genotype at the ACE polymorphism were at about two-fold increased risk for CVD.

(23andMe customers can check their data using SNP rs1799752 in the Browse Raw Data feature.  Data for this SNP is available only to those customers who received their data after 9/1/08, or upgraded their accounts since that date.)

Although these results may eventually help scientists understand the exactly how migraine and CVD are related to ACE, a lot of work remains to be done.  The authors themselves warn that larger studies will be needed and that their research did not take into account environmental or other genetic risk factors.  They also note that their study sample was restricted to Caucasian women 45 years old and older, which may mean that their results are not applicable to the population as a whole.  Finally, in both women with and without migraine, the proportion of the different genotypes (DD/DI/II) differed from what would be expected in the population, suggesting that there may have been flaws in the study.

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Lifestyle factors such as smoking or a high-fat diet are well-established contributors to heart attack risk, because they encourage the accumulation of sticky plaques inside the arteries that supply the heart with oxygen- and nutrient-rich blood.

Though genetics plays an almost equal role in the accumulation of plaques in the coronary arteries, the specific genes involved in the process are largely unknown.  Only one region of DNA on chromosome 9 has consistently been linked to heart disease.

(23andMe customers can learn more in the Heart Attack Research Report.)

Now five studies, published online yesterday in the journal Nature Genetics, have identified a bumper crop of genetic variations associated with coronary artery disease (the build up of plaque) and heart attack.  Although more work will be needed to confirm these associations and figure out exactly how they affect risk, these results are a major step forward in understanding the biology of heart disease. Eventually the variations identified in these and future studies may be useful for prediction, prevention or treatment of coronary artery disease and heart attack.

Four of the studies looked at the effects of individual SNPs on coronary artery disease or heart attack. 23andMe customers can check their data for many of these using the information at the end of this post. The fifth study looked at the effect of a combination of four SNPs.  23andMe cannot currently provide customers with the type of data described in this study.


Note: In each table, “Effect” refers to the increase in odds for each copy of the risk version compared to two copies of the non-risk version of the SNP.


Study: Myocardial Infarction Genetics Consortium
Early-onset heart attack (men 50 years old or younger, women 60 years old or younger)
Cases: More than 12,000
Controls: More than 12,000
Populations studied: European ancestry; United States, Sweden, Finland, Spain, Italy, U.K., Germany, Ireland and Iceland

Study: Gudbjartsson et al.
Heart Attack
Cases: 6,650
Controls: 40,621
Populations studied: European ancestry; Iceland, United States, New Zealand and Italy

Study: Erdmann et al.
Coronary Artery Disease
Cases: 19,407
Controls: 21,366
Populations studied: European ancestry; United States, Sweden, Finland, Spain, Italy, U.K. and Germany

Study: Ozaki et al.
Heart Attack
Cases: 3,337
Controls: 3,891
Population studied: Asian ancestry; Japan

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Every year, about half of the more than one million people in the United States who have a heart attack survive. But because the first heart attack increases their risk for another one, these people must make major adjustments in their lives to keep their hearts healthy in the future.

In addition to adopting a healthy diet, quitting smoking and losing weight, most people who’ve had a heart attack take medications to help further reduce their risk. Clopidogrel — sold under the trade names Plavix, Iscover, Clopilet and Ceruvin — is a drug commonly prescribed (often in combination with aspirin) to help prevent platelets in the blood from forming clots that can block blood flow to the heart.

Clopidogrel is converted into its active form once it is inside the body. But some people carry genetic variants that reduce the activity of an enzyme central to this conversion process, which in turn reduces the amount of active clopidogrel in the bloodstream and the effectiveness of the drug in preventing clots. Three reports published online this week – two in the New England Journal of Medicine and one in The Lancet – show that these genetic variants can increase the chances that a patient will suffer a second major cardiovascular event.

Jessica Mega and co-workers from Brigham and Women’s Hospital and Harvard Medical School in Boston tracked 1,477 subjects who had had unstable angina or a heart attack and were taking clopidogrel.

Their results, published in NEJM, showed that those people who carried one or more copies of a function-reducing variation in the CYP2C19 gene that (referred to as *2, *3, *4 and *5) had 1.53 times the risk of having a heart attack, stroke or dying from cardiovascular causes compared to non-carriers. The risk of a stent-blocking clot (in those patients who had stents implanted during angioplasty to keep their arteries open) was increased three-fold.

The second NEJM report, from researchers at several Paris hospitals led by Tabassome Simon, showed that in a group of 2,208 heart attack patients taking clopidogrel, carrying two CYP2C19 variants (any combination of *2, *3, *4, or *5) led to a 1.98 times increased risk of heart attack, stroke or death from any cause. Among the 1,535 patients who underwent angioplasty while in the hospital, having two function-reducing CYP2C19 variants increased the risk of cardiovascular events by 3.58 times.

Unlike the study from Mega et al, Simon and colleagues did not see an increased risk in those people with only one copy of a CYP2C19 function-reducing variant.

Finally, Jean-Philippe Collet and colleagues (also from Paris, France) followed the outcomes for 259 young (< 45 years old) heart attack patients taking clopidogrel. Their results, published in The Lancet, showed that having one or two copies of the CYP2C19*2 variant increased the risk of a second heart attack by 4.54 times. The risk of a stent-blocking clot increased 6.02 times.

Collet et al did not investigate the other CYP2C19 variants included in the other reports.

(23andMe customers can check whether they carry any of the CYP2C19 variants mentioned in these reports, except for CYP2C19*5, using the Browse Raw Data feature. See the table at the end of this post for more information.)

Although the magnitude of the effect of CYP2C19 variants was different in each report, all three did show that versions of the CYP2C19 gene that reduce its ability to activate clopidogrel also increased the risk of a second cardiovascular event in those patients who have already suffered one. Based on these results, both Simon et al and Collet et al suggest that genotyping patients might be a good alternative to the current practice of monitoring their platelet response to clopidogrel.

But in a commentary accompanying the report in The Lancet, Dr. Robert Storey of the Cardiovascular Research Unit at the University of Sheffield School of Medicine, UK, argues that testing platelet function in patients is faster than genotyping, and has the added benefit of finding patients who are not responding to clopidogrel due to factors other than CYP2C19 variants, such as age, diabetes, renal failure and cardiac failure.

“Genotyping of patients with acute coronary syndrome is not necessarily the appropriate solution without further work to validate such an approach,” he writes.

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Climate is already known to be partially responsible for the variations seen in body shape and size among humans – it’s no accident that Arctic Inuit tend to be short and squat while East African Maasai are long and lean.

Researchers at the University of Chicago recently hypothesized that climate might also have influenced genetic differences in metabolism.

“As some populations migrated out of Africa to much cooler climates, there would have been pressure to adapt to their new settings by boosting the processes that produce and retain heat,” said Anna Di Rienzo, a professor of genetics at the university.

A study published by Rienzo and her colleagues in today’s PLoS Genetics shows that genetic adaptations to colder climates do seem to affect susceptibility to many common metabolism-related disorders.

The scientists tested their idea by looking at SNPs in metabolism genes in 54 populations from around the world. They found that as a group, variations in these genes are correlated with climate measures such as temperature, humidity, and UV exposure.

Some of the variations that increased in frequency as people moved farther out of Africa have turned out to be harmful in the modern world. For example, the protein made by the FABP2 gene helps the body transport, absorb, and metabolize fats. A version of a SNP in this gene that is more prevalent in populations at higher latitudes causes the protein to bind fats more tightly and has been associated with increased insulin resistance, higher cholesterol and triglyceride levels, and more abdominal fat.

But adaptations to colder weather that took place thousands of years ago don’t necessarily doom a population to a higher risk for disease today. A version of a SNP in the PON1 gene (which encodes a protein involved in dilation of blood vessels) that is more common in populations from cooler regions is associated with decreased risk for coronary artery disease, stroke, and heart attack.

According to the study’s authors, whether a variation increases or decreases risk for metabolic disorders will depend on exactly how the variation helped people deal with their new environment. For example, a variation in the LEPR gene probably helped early humans generate more body heat. Today this variant is associated with lower BMI. But the variation in the FABP2 gene discussed above, probably helped people stay warm by increasing BMI.

The frequencies of the two different versions of SNP rs662 in the PON1 gene are shown as a pie chart for each of the tested populations against a background map showing summer surface solar radiation. (From Hancock et al. (2008) Adaptations to climate in candidate genes for common metabolic disorders. PLoS Genet 4(2): e32. doi:10.1371/journal.pgen.0040032.g001)

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One of the much-heralded claims of the post-genomic era is that personal genetic information may allow medical treatments to be tailored to an individual’s genetic makeup. While we are not there yet, a trio of new studies on heart disease may just have brought us one step closer. The studies were the product of a collaboration between researchers at Harvard Medical School and Celera (the company that helped spur completion of the public Human Genome Project).

In the first study of over 25,000 women, those with the GG or AG genotypes at the SNP rs20455 were found to have a slightly increased chance of having a heart attack—about 34% higher than those with the AA genotype. (This study confirmed at least two other preliminary findings that this SNP, which is in the gene KIF6, is associated with heart disease.)

A second study of about 3,000 subjects further confirmed the first finding, and also examined whether the SNP was associated with the outcome of treatment with the cholesterol-lowering drug pravastatin. As other studies have reported, those with the GG or AG genotypes were found to be at higher risk of having a heart attack than those with the AA genotype. But when treated with pravastatin, the risk of heart attack for people with GG or AG was substantially reduced—approximately equal to that of the lower-risk AA group. (Pravastatin treatment had little or no effect on those with the AA genotype.)

Lastly, a third study of about 4,000 subjects compared how rs20455 affected differences in outcomes for people given the standard-dose pravastatin therapy versus high-dose treatment with atorvastatin, another anti-cholesterol drug. Those with the AA genotype saw no additional benefit of receiving the more intense atorvastatin treatment compared to the standard pravastatin treatment. But people in the study with GG or AG did see a significant reduction in their risk of having a heart attack, cutting their risk by about 40% over two years.

23andMe customers may examine their genotype at rs20455 in the Genome Explorer (now called Browse Raw Data) and compare their genetic data to that of the studies in this article. Keep in mind, however, the points made in the introduction to this SNPwatch article.

In addition to the SNPwatch reminder, remember that genetics are only one factor that physicians may consider when prescribing preventive medications for heart disease or any condition. If you have concerns or questions about what you learn through 23andMe, you should contact your physician or other appropriate professional.

Update [2008/01/24]: Although our Gene Journal article on heart attacks (now called Health and Traits) does not currently cover this SNP, we believe that this association has been replicated sufficiently enough to include in the article–we’ll get to it as soon as we can!

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