February 20, 2001
UW study indicates possible drug-gene interaction associated with heart
With the completion of a study by researchers at the University of Washington, the relationship between hormone replacement therapy and myocardial infarction (heart attacks) is a little clearer. The study, published in the Feb. 21 edition of the Journa of the American Medical Association, shows a possible link between the presence of a genetic variant associated with blood clotting and the risk of non-fatal myocardial infarction (MI) in hypertensive women taking hormone replacement therapy (HRT).
The lead author of the study is Dr. Bruce M. Psaty, a professor of medicine, epidemiology and health services and co-director of the UW’s Cardiovascular Health Research Unit. Psaty’s co-investigators are Drs. Nicholas L. Smith, Rozenn N. Lemaitre, Susan R. Heckbert, all from the University of Washington; Andrea Z. LaCroix, from Group Health Cooperative; and Hans L. Vos and Frits R. Rosendaal, from the Leiden University Medical Center, the Netherlands. This study was funded by grants from the National Heart, Lung and Blood Institute and the American Heart Association.
Psaty and his co-authors studied the prothrombin gene in a case-control study conducted at Group Health Cooperative, a health system based in Seattle. Prothrombin (factor II) is a protein essential for the clotting of blood. The prothrombin gene variant (G20210A) occurs in 2 to 4% of the population and increases the risk of blood clots in the legs.
The investigators studied 232 post-menopausal women who suffered a first non-fatal MI between 1995 and 1998. The control group included 723 postmenopausal women matched to the cases by age, calendar year of the cardiac event and hypertension status.
In women with hypertension, the effects of HRT on MI risk depended on the prothrombin gene. Among women who did not have the genetic variant, HRT users had a slightly lower risk of MI than women who did not use HRT. Among women with the prothrombin gene variant, however, HRT users had an eight-fold higher risk of MI than women who did not use HRT. Although the number of women with the prothrombin variant was small, the MI risk associated with HRT use differed markedly between those with and without the prothrombin variant.
“The finding of a drug-gene interaction is a potentially important application of recent work on the human genome, but it needs to be confirmed in other studies,” Psaty said. “At this time, there is insufficient evidence to consider screening postmenopausal women for this genetic variant.”
The interaction persisted when the investigators adjusted for many known risk factors for MI, and it was specific to the prothrombin variant.
“This is the first study showing a link between genetic clotting abnormalities and MI in women on HRT,” said Dr. Frits R. Rosendaal, professor and chairman of clinical epidemiology at Leiden University. “Increasingly, evidence suggests that several genetic variants in clotting factors have an important role in promoting vascular diseases.”
The researchers looked for the prothrombin-HRT interaction in women without hypertension, but did not find evidence of it.
If the study’s findings are confirmed or extended in future studies, physicians may use the results of one or more genetic tests to better predict the major health risks and benefits of hormone replacement therapy in individual postmenopausal women.
“To recommend genetic screening, we would need to know that the health benefits exceed the risks,” Psaty noted. “Now that we have the sequence of the human genome almost in hand, the task of assessing its clinical usefulness is just beginning.”
The test for the prothrombin variant is a research test. Women who are taking HRT should not stop taking their medications. If they have questions about HRT, they should consult their physicians.