Gene Influences Response to Blood Pressure Medication

Variation in a single gene directly affects how patients with hypertension respond to the most frequently used medication for high blood pressure, researchers at the Mayo Clinic and The University of Texas Health Science Center at Houston have found.

The findings, reported in a recent issue of the journal Hypertension, are among the first to pinpoint a connection between a patient's genetic makeup and the patient's response to a medication for a common disease.

Lead author Dr. Stephen T. Turner, hypertension specialist at the Mayo Clinic in Rochester, Minn., and senior author Dr. Eric Boerwinkle, director of the Human Genetics Center at UT-Houston, led a team that examined the relationship between the GNB3 gene and blood pressure response to the diuretic hydrochlorothiazide, a first-line medication for high blood pressure. They found that differences in the gene significantly affect the decline in 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.

"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," Dr. Boerwinkle said. "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."

"We have many good medications to treat hypertension, but none of them helps every patient," Dr. Turner said. "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."

The research team enrolled 397 volunteers with hypertension in a study that also measured nine 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 Dr. Gary Schwartz at the Mayo Clinic, and by Dr. Arlene Chapman, associate professor at the Emory University School of Medicine's Renal Division in Atlanta, Ga. Genotyping and genetic analysis were conducted by Dr. Boerwinkle at UT-Houston, where he also directs the Research Center for Human Genetics at the Institute of Molecular Medicine for the Prevention of Human Disease.

Research focused on the C825T polymorphism on the GNB3 gene. The human DNA sequence consists of four chemical letters - A, T, G, and C. At the 825th letter in the DNA coding that makes up the GNB3 gene, some people have two Ts, others have two Cs and others have a T and a C. These differences influence the function of the GNB3 protein. The project showed that the drug worked for all three groups, but it was 60 percent to 78 percent more effective for those who are TT compared to those who are CC.

The average drop in systolic blood pressure for TT patients was 16.3 millimeters of mercury on the standard blood-pressure scale, compared with 13.6 for the CT patients and 10.2 for the CC group. Results were similar for diastolic blood pressure, with TT at a 10.5 decline, CT at 7.8 and CC at 5.9.

The GNB3 variation was the second strongest of nine measured predictors of diastolic pressure and the fourth strongest of systolic blood pressure. The magnitude of the gene's effect was similar to that of other previously identified predictors of diuretic responsivity, including race, gender, and measures of kidney function, the authors note. When all predictors were mathematically analyzed together, genetic variation remained a statistically significant factor for both systolic and diastolic blood pressure.

Overall, Drs. Boerwinkle and Turner noted, all predictors combined accounted for 32 percent of blood pressure variation among individuals. The study provides the basis for further investigation of genes that may explain the remaining variation.

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©2006 Texas Medical Center

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