Genetic Variance in the Response to Diuretic Therapy for Hypertension
June 1, 2002 5 minutes read
Genetic Variance in the Response to Diuretic Therapy for Hypertension
Abstract & Commentary
Synopsis: Diuretics are safe and effective in preventing complications of hypertension and are "the preferred first-time medication" for treatment of hypertension.
Source: Psaty BM, et al. JAMA. 2002;287: 1680-1689.
A recent report suggests that pharmacogenetic analysis may be used in the future in drug selection for common conditions. This study, from the Cardiovascular Health Research Unit in Seattle, asked the question whether a genetic variance in a-adducin, a gene associated with renal sodium balance, might result in different responses to a diuretic in carriers of a variant allele in whom high rates of renal tubular sodium reabsorption have been documented. The Gly460Trp variant of the a-adducin gene has been associated with renal sodium retention and salt-sensitive hypertension. A polymorphism has been described as a potential cause of hypertension in some populations. Psaty and colleagues hypothesized that carriers of 1 or 2 copies of the variant allele, who have increased renal sodium reabsorption, would have an augmented response to diuretics. They further asked whether the phenotype of salt-sensitivity, independent of blood pressure, might be related to events. This is a population-based case-control study in hypertensive patients, using an analysis of hypertension agents. The primary hypothesis is that pharmacologic treatment of hypertension with a diuretic would have a lower event rate in carriers of the a-adducin variant compared to normal, wild-type subjects. Cases from the Group Health Cooperative (GHC) in Seattle were identified with treated hypertension that had survived a myocardial infarction (MI) or stroke between 1995 and 1998. Controls were identified using a stratified random sample, and were matched with the MI cases by age, sex, and year of the index event. Controls were enrolled at a ratio of 2-to-1 for men and 3-to-1 for women. Careful review of the GHC outpatient medical records, blood sampling, and medical interview were carried out using the GHC computerized pharmacy database information on anti-hypertensive therapy. Users of a specific drug had to be taking the agent for at least 30 days prior to the index event date; the majority of subjects used these agents for years. Compliance was assumed to be 100%. Hypertensive drugs analyzed included diuretics, beta blockers, ACE Inhibitors, calcium channel blockers, and other vasodilators. The adducin-variant was assayed by using standard PCR techniques. Participants were classified as either homozygote carriers of the adducin-wild- type genotype (normals) or those with 1 or 2 copies of the a-adducin-variant TRP460 allele. Odds ratios were subsequently calculated for cases and controls. The primary analysis consisted of 206 MI cases, 117 stroke cases, and 715 controls. There were same baseline differences between cases and controls, with a greater burden of CAD risk factors in those who had an MI. The frequency of the adducin-gene variant was > 35% in both groups. Current users of a diuretic had over 10 years of exposure vs. 3.7 years for noncurrent users.
Results: Among the wild-type carriers, ie, normals, the use of diuretics for hypertension was not associated with an increased risk of MI or stroke. For prior users, the adducin-variant was associated with a modest increase in risk (odds ratio [OR], 1.56; confidence interval [CI], 1.09-23). However, for adducin-variant carriers who took diuretics, the odds ratio was reduced by 33% (CI, 0.51-1.17). Diuretic therapy in the 385 carriers of the adducin-variant was associated with a markedly lower risk of major vascular events, but there was no association of such events with other hypertensive drugs. The risk reduction OR was 0.49; CI 0.32-0.77. The data were comparable for both stroke and MI. Other medications did not influence the results, and "the interaction between diuretic use and the adducin-variant was specific to diuretics," and was more pronounced in the homozygotes. In fact, homozygotes that took diuretics had no history of an MI or stroke. Psaty et al conclude that there is a significant interaction with the adducin-Trp460 variant and use of diuretics with respect to the risk of a combined outcome of first nonfatal MI or stroke, whereas among carriers of the wild-type genotype, diuretic therapy was not associated with any effect on risk. Risk reduction among the carriers was robust at approximately 50%, and was the specific to diuretic therapy. Psaty et al admit that the mechanism by which diuretic use reduces the risk of MI or stroke is uncertain, but is in some way related to the effects of diuretics on sodium excretion and absorption. Diuretics should reverse the physiologic status of the variant patients who have an increased sodium reabsorption state. "Salt-sensitivity, independent of blood pressure, has been associated with an increased risk of cardiovascular events." Psaty et al point out that other genetic polymorphisms have been associated with increased rates of hypertension. They believe that identification of various genes involved in blood pressure control may ultimately result in novel drug class design. Future research may improve "the safety and efficacy profile of commonly used medications." They suggest that if this data can be validated, future efforts to screen hypertensive patients for selective genetic polymorphisms might be a practical way to individualize drug treatment and maximize effectiveness as well as safety. Finally, they conclude that diuretics are safe and effective in preventing complications of hypertension and are "the preferred first time medication" for treatment of hypertension.
Comment by Jonathan Abrams, MD
I believe that this is an exciting study, as it appears to suggest a major role for pharmacogenetics influencing physician choice of drug therapy for hypertension. Mechanistically, there are little data available; the study suggests that individuals carrying 1 or 2 copies of the variant gene, when exposed to a diuretic for a protracted period of time, have a decreased risk in developing an MI or a stroke. There was no relationship found for the gene polymorphism for any other class of hypertensive agent. Other genetic variants have been identified, particularly the angiotensin insertion-deletion variant polymorphism, which has been extensively studied. The concept that a "simple drug" such as a diuretic might have different long-term effects on major vascular events, depending on a particular genetic variant is both fascinating and stimulating. In that the individuals with the gene variant are common and had a 50% lesser likelihood of having a stroke or MI during the observational period if treated with a diuretic, it seems clearly worth confirming these data. If these turn out to be valid, this data would predict a major role for genotyping to guide hypertension therapy in the near future.
Dr. Abrams, MD is Professor of Medicine, Division on Cardiology, University of New Mexico, Albuquerque.
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