Feb. 28, 2001 ROCHESTER, MINN. -- Variation in a single gene affects how patients respond to a frequently used medication for high blood pressure, researchers at Mayo Clinic, Emory University School of Medicine and the University of Texas Health Sciences Center at Houston have found.
The findings, reported in the February issue of the journal Hypertension, are among the first to pinpoint a connection between a patient’s genetic makeup and the effectiveness of a medication for a common disease. The team examined the relationship between the GNB3 gene and blood pressure response to the diuretic hydrochlorothiazide (HCTZ), a first-line medication for high blood pressure. They found that differences in the gene significantly affected the decline in both systolic and diastolic blood pressure produced by the drug.
Hypertension afflicts an estimated 50 million Americans and plays a major role in cardiovascular disease, stroke and renal failure.
"We have many good medications to treat hypertension, but none of them helps every patient," says Stephen T. Turner, M.D., a Mayo Clinic hypertension specialist and the lead author of the study. "Only about 50 percent of patients will respond to any single drug like HCTZ. Therefore, many patients may have to try several different drugs or combinations before gaining control of their blood pressure. If we can understand why patients respond to some drugs but not to others, we will be able to prescribe medications at the outset that are more likely to be effective and avoid the current trial and error process of drug selection."
"This project highlights one of the most promising applications of our rapidly increasing genetic knowledge -- the ability to more precisely target the medications that we already have," says Eric Boerwinkle, Ph.D., director of the Human Genetics Center at the University of Texas Health Sciences Center in Houston, Tex. "A drug’s effectiveness can vary tremendously from patient to patient. Genetic differences have long been suspected as an important cause of this variation. By establishing that this gene is a significant predictor of response to HCTZ, we’ve taken another step toward being able to tailor drug therapy to individual patients."
The research team enrolled 397 volunteers with hypertension in a study that also measured other predictors of response to the medication, such as pretreatment blood pressure, race and age, as well as the effect of the G protein B3-subunit gene, or GNB3. The clinical trials were conducted by Dr. Turner and colleague, Gary Schwartz, M.D., at Mayo Clinic in Rochester, Minn., and by Arlene Chapman, M.D., associate professor at the Emory University School of Medicine Renal Division, Atlanta, Ga. Genotyping and genetic analysis were conducted by Dr. Boerwinkle in Houston.
The team analyzed blood pressure changes among patients with different combinations of the two variations of the GNB3 (C and T) gene. The project showed that the diuretic was 60 to 78 percent more effective in reducing blood pressure for the group with two copies of the T-variant of the gene compared to those with two copies of the C-variant of the gene. Of the nine predictors of blood pressure measured separately in the study, the genetic variation was the second-strongest predictor of diastolic pressure and the fourth strongest of systolic blood pressure.
"This single gene doesn’t explain all of the variation in response to HCTZ, but it does provide part of the solution," says Dr. Turner. "With all known factors combined, we can account for about 32 percent of blood pressure variation among individuals. The current study provides a solid basis for further investigation into other genes that may explain the rest, and which may someday enable us to choose medications that will have a much higher probability of effectiveness for a given patient."
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