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April 2, 2002

UW study links gene to success of a treatment for high blood pressure

Someday, people taking medications for high blood pressure may undergo genetic screening tests that help identify which drug therapies are best for them. University of Washington researchers and colleagues found that people with hypertension who have a particular genetic variant were twice as likely to avoid heart attacks and strokes if they took a diuretic medication.


The study will be published in the April 3 edition of the Journal of the American Medical Association. About 50 million Americans have high blood pressure; about 25 million take medication for it.


“If these findings are confirmed in other studies, screening for the adducin variant could identify hypertensive patients especially likely to benefit from low-dose diuretic therapy,” says Dr. Bruce M. Psaty, a professor of medicine, epidemiology and health services and co-director of the UW’s Cardiovascular Health Research Unit.


The test for the adducin variant is now a research tool, and Psaty says it’s not appropriate for clinical testing. Additional studies need to define the risks and benefits of genetic testing.


Psaty and co-authors studied the alpha-adducin (pronounced A-dew-sin) gene in a case-control study conducted at Group Health Cooperative, a large health maintenance organization based in Seattle. Adducin is a protein linked to the inner surface of cell membranes, and one adducin genetic variant (Gly460Trp) is known to increase sodium retention by the kidney. High-salt diets, as well as sodium retention, are one cause of high blood pressure. (Table salt is sodium chloride.)


Diuretics are currently recommended as first-line drug therapy for hypertension by the U.S. Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Diuretics lower blood pressure by making the kidney excrete sodium. The idea for the study arose from the observation that diuretics and the adducin variant have opposing effects on sodium handling by the kidney.


The investigators studied 323 hypertensive patients who suffered a first non-fatal heart attack or stroke between 1995 and 1998. The control group included 715 hypertensive patients matched to the cases by age and sex. All participants were taking medications for their high blood pressure.


About one-third of the people in this study had the adducin variant. Diuretics were compared with other drug therapies. The effect of diuretic therapy on the risk of heart attack or stroke depended on the adducin gene variant. Among hypertensive patients who had the normal (wild type) adducin gene, diuretics did not differ from other antihypertensive medications. Among patients with the adducin gene variant, diuretic therapy was associated with a 50 percent lower risk of heart attack or stroke than other blood pressure medications.


“The finding of an adducin-diuretic interaction is a potentially important application of recent work on the human genome, but it needs to be confirmed in other studies,” Psaty said.


The interaction persisted when the investigators adjusted for many known risk factors. It was similar in subgroups, and it was specific to diuretics. “Most importantly,” Psaty says, “low-dose diuretics prevent complications such as heart attack and stroke.” While they may be particularly effective in patients with the adducin variant, large long-term clinical trials have consistently shown that low-dose diuretics are safe and effective for the treatment of high blood pressure in all people. They are also inexpensive.


“If you are taking medicines for high blood pressure, and if you are not on a low-dose diuretic,” Psaty adds, “it is reasonable to ask your physician, ‘Why not?’”


Psaty’s co-investigators are Drs. Nicholas L. Smith, Rozenn N. Lemaitre, Susan R. Heckbert, Alexander Reiner, David Siscovick, Joshua Bis, Thomas Lumley and W.T. Longstreth, Jr, all from the University of Washington; and Hans L. Vos and Frits R. Rosendaal, from the Leiden University Medical Center, the Netherlands. This work represents part of a long-standing collaboration between the UW and the Leiden group. Psaty and Heckbert are also affiliate investigators at Group Health’s Center for Health Studies.


This study was funded by grants from the National Heart, Lung and Blood Institute and the American Heart Association.