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Diuretic Therapy, the -Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated Hypertension

Bruce M. Psaty, MD,PhD; Nicholas L. Smith, PhD; Susan R. Heckbert, MD,PhD; Hans L. Vos, PhD; Rozenn N. Lemaitre, PhD; Alexander P. Reiner, MD,MPH; David S. Siscovick, MD,MPH; Joshua Bis; Thomas Lumley, PhD; W. T. Longstreth, Jr, MD,MPH; Frits R. Rosendaal, MD,PhD

JAMA. 2002;287:1680-1689.

Context  A genetic variant in -adducin has been associated with renal sodium reabsorption and salt-sensitive hypertension. Whether this genetic variant modifies the effect of diuretic therapy on the incidence of myocardial infarction (MI) and stroke is unknown.

Objectives  To estimate the interaction between -adducin and diuretic therapy on the risk of MI or stroke. Specifically, we hypothesized that in participants with treated hypertension, the risk of MI or stroke associated with diuretic use would be lower in carriers of the adducin variant than in carriers of the adducin wild-type genotype.

Design, Setting, and Participants  Population-based case-control study of patients enrolled in a health maintenance organization, treated pharmacologically for hypertension, and genotyped as homozygous carriers of the adducin wild-type genotype or carriers of 1 or 2 copies of the Trp460 variant allele. Cases had a first nonfatal MI (n = 206) or stroke (n = 117) between January 1995 and December 1998. Controls (n = 715) were a stratified random sample of pharmacologically treated hypertensive patients who were matched to MI cases by age, sex, and calendar year.

Main Outcome Measure  Risk of the combined outcome of first nonfatal MI or stroke.

Results  The adducin variant was present in more than one third of the participants. Among the 653 carriers of the adducin wild-type genotype, diuretic therapy was not associated with the risk of MI or stroke (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.78-1.52). Among the 385 carriers of the adducin variant allele, diuretic therapy was associated with a lower risk of the combined outcome of MI and stroke than other antihypertensive therapies (OR, 0.49; 95% CI, 0.32-0.77). The OR in carriers of the adducin variant was less than half of the OR in carriers of the wild-type genotype (P = .005). The case-control synergy index (SI) was 0.45 (95% CI, 0.26-0.79) for the combined outcome of MI and stroke. The point estimates of the diuretic-adducin interaction were similar in separate analyses of MI (SI, 0.41; 95% CI, 0.21-0.80) and stroke (SI, 0.53; 95% CI, 0.24-1.19). The diuretic-adducin interaction was not confounded by traditional cardiovascular risk factors, was specific to diuretic therapy but not present for other major antihypertensive drug classes, and did not differ substantially between subgroups defined by age, sex, race, diabetes, and history of cardiovascular disease.

Conclusions  In carriers of the adducin variant, diuretic therapy was associated with a lower risk of combined MI or stroke than other antihypertensive therapies. If these findings are confirmed in other studies, this large subgroup of the hypertensive population may be especially likely to benefit from low-dose diuretic therapy.

Author Affiliations: Cardiovascular Health Research Unit, Departments of Epidemiology (Drs Psaty, Smith, Heckbert, Reiner, Rosendaal and Mr Bis), Medicine (Drs Psaty, Lemaitre, Siscovick), Biostatistics (Dr Lumley), Neurology (Dr Longstreth), and Health Services (Dr Psaty), University of Washington, Seattle; and Departments of Hematology (Drs Vos and Rosendaal) and Clinical Epidemiology (Dr Rosendaal), Leiden University Medical Center, Leiden, the Netherlands.

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