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Gene at heart of bad outcomes in high blood pressure patients


Finding advances efforts to tailor drugs to individual patients

Having high blood pressure and a particular genetic alteration dramatically increases the risk of heart attack, stroke or death, and may explain why some hypertensive patients fare worse than others - even if they take the same medication, University of Florida researchers announced this week.

The discovery, reported at the annual Scientific Sessions of the American Heart Association, brings scientists a step closer toward determining how certain genes influence the development of hypertension and the bad outcomes associated with the condition. Just as discriminating shoppers buy made-to-order suits to flatter their figure, this type of research may someday enable patients to seek out medicine tailored to fit, based not on their size and shape but on their genetic makeup.

UF researchers studied about 5,700 patients ages 50 and older who were participating in a National Institutes of Health-funded substudy of the International Verapamil SR-Trandolapril study, or INVEST-GENES. Other scientists had previously found that hypertensive patients with a certain version of the alpha-adducin gene were less likely to suffer a heart attack or stroke if they were taking a diuretic.

"Specifically, their data suggested that one genotype group benefited from the diuretic and had a reduction in heart attack and stroke, while the other genotype group did not," said Julie Johnson, Pharm.D., director of the UF Center for Pharmacogenomics and chairwoman of the department of pharmacy practice at UF’s College of Pharmacy. "We felt we had an ideal population for trying to replicate this finding, which if true could have important clinical implications.

"In our study, carriers of the genetic variation had an approximately 43 percent higher risk of death, heart attack or stroke," she said. "Thus, this helps us piece together the puzzle of the various genes that lead to some people having worse outcomes than others when they have hypertension."

Genes likely determine nearly half one’s risk of developing hypertension, and factors such as diet, age, health status and the environment determine the rest. Similarly, certain genes are associated with the risk of the adverse consequences of hypertension, such as heart attack, stroke and kidney failure, said Johnson, a member of the UF Genetics Institute.

"One of the goals of our research is to identify the genes that are related to patient-to-patient differences in response to medications," Johnson said. "Personalizing drugs based on genetic makeup instead of taking a trial-and-error approach could lead to safer, more effective treatments for individual patients."

About 65 million Americans have high blood pressure, and another 25 million are at high risk of developing hypertension in the next decade, Johnson said. Elevated blood pressure is associated with kidney disease and up to half of all cases of coronary artery disease, the No. 1 killer of men and women in the United States. Many patients fail to achieve targeted blood pressure goals.

In the INVEST substudy, nearly a third of the participants were carriers of the tryptophan version of the alpha-adducin gene, a protein associated with the movement of ions, especially sodium, across cells. In these individuals, the amino acid glycine has been swapped with the amino acid tryptophan. Up to 40 percent of the population carries at least one copy of the tryptophan form of the gene.

In the UF study, those with this version had a 43 percent higher risk of heart attack, stroke or death than those with the glycine form in the 2 ½ years after the study began; 258 patients, about 5 percent, experienced a heart attack or stroke, or died. But unlike previous research, the UF study did not show that patients with the glycine form benefited more from diuretics, which help lower blood pressure by ridding the body of excess salt and water.

"We were not able to show any relationship between the genetic variations and benefits associated with diuretic therapy," Johnson said. "Thus, our data suggest that we would not use this genetic information to help determine who should get a diuretic. However, it does provide us clues into at least one gene that likely places people at risk for death, heart attack and stroke, and so perhaps in the future this information can be used to be more aggressive in the preventive therapies for these individuals."

As researchers learn more, they hope to better understand the complex interplay between genes, disease development and the treatments that work best depending on one’s DNA. For now, identifying patients at risk remains a challenge, and treatment is often inadequate, Johnson said.

"There are five first-line drug classes, with probably an average of seven to eight drugs in each class, then an additional half-dozen or so other drug classes that aren’t considered first-line," Johnson said. "This means there are many choices for drug therapy in hypertension - a good thing - but also adds to the trial-and-error element of finding the right drug for the right person, as any specific drug has only about a 50 percent chance of being effective in a specific patient."

Identifying genetic risk factors is only the first step, said epidemiologist Sharon Kardia, Ph.D., director of the Public Health Genetics Program at the University of Michigan School of Public Health.

"Large research studies need to be undertaken to prove that genetic risk can be reduced through medical or public health interventions. Second, this whole new realm of genomic medicine greatly expands the responsibilities of doctors, nurses and pharmacist to assure the proper use of genetic information in prescribing, dispensing and administering drug therapies," Kardia said. "Lastly, we have to tread lightly until we have assurances that people’s genetic information will be properly protected so that identifying someone as more expensive or difficult to treat won’t result in insurance or perhaps job discrimination. As Dr. Johnson’s research illustrates, we now have good evidence that we should be investing in genetics education, regulation and social engagement so that we can move these results to the next level - namely, decreasing health-care costs and saving lives."

Melanie Ross | EurekAlert!
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