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Meanwhile, many other people carry a genetic variant that results in increased CYP2C19 activity, and these individuals can often get by with lower doses of the clot-preventing drug.
The frequencies of the most common mutations known to limit Plavix’s efficacy are similar among Jewish and non-Jewish populations. But Stuart Scott and his colleagues at the Mount Sinai School of Medicine in New York have found that around 2% of both Ashkenazim and Sephardim carry a loss-of-function variant. That variant is around four times more common in Jews than in the general population and often goes unchecked by today’s standard tests. Unless this genotype — known in medical circles as CYP2C19*4B — is accounted for, says Scott, “you’ll classify people incorrectly,” with potentially life-threatening consequences.
Thus, even if Siegel’s doctors had ordered a genetic test for him, that test might not have included DNA variants that are relevant to his ethnic background, and the results could have been erroneous.
Scott’s team reported the findings last year in The Pharmacogenomics Journal.
The importance of genetics for drug response can also be seen in people’s response to the anticoagulant warfarin, a drug that often requires close monitoring and frequent dose adjustments.
Although the proportion of Ashkenazi Jews who are classified as “sensitive” to the drug is similar to that in other Caucasian populations, the fraction of warfarin-sensitive Sephardim is about 50% higher, meaning they require lower doses of the blood thinner. Conversely, around one in 25 Ashkenazim has a genetic mutation that renders them warfarin “resistant,” which means they need higher doses of the 60-year-old generic drug than typically prescribed, Scott’s group has found. About one in 200 Sephardim has this variant.
Considering that warfarin is the leading cause of prescription drug-related emergency room visits, knowing a person’s genetics — and tailoring drug therapy accordingly — could save thousands of lives each year.
“Warfarin dosing is tricky,” Shuldiner says. “In patients in whom we know the genotype, we can tailor warfarin dosing more finely and achieve therapeutic targets more quickly.” Indeed, a study published earlier this year in the journal Circulation found that genetics-guided therapy helped people on warfarin stay in the therapeutic range for significantly longer than people who received the current standard of care.
More than 100 drugs — ranging from cancer medicines to antidepressants — now contain some sort of information on their labels about how genetic biomarkers can help inform dosing, response variability or risk for adverse events. Yet few other drug-associated genes have been characterized specifically in Jewish populations. That’s why David Gurwitz, director of the National Laboratory for the Genetics of Israeli Populations at Tel-Aviv University, together with colleagues from the Palestinian Authority and Jordan, has been looking for funding to investigate the variation inherent in major drug metabolizing genes among the ethnic populations of the Middle East.
“We don’t know enough about the genetic variation that is important for drug response in Jews,” says Gurwitz. “There could be many cases where there are large percentages of alleles [in Jews] that are not good for certain drugs. We just don’t know.”
For Siegel, knowing that information could be critical. After two heart attacks and with a daily regimen of five drugs for his heart condition, ensuring that those prescriptions match his genetic profile could hold the key to preventing another major medical crisis. But Siegel says he trusts his doctors and is not getting worked up about his medications. There are no plans to test his genetics.
Elie Dolgin is a news editor with the journal Nature Medicine, in Cambridge, Mass. Contact him at firstname.lastname@example.org