INTRODUCTION: The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. OBJECTIVE: The aim of the study was to determine whether the alpha-adducin 460Trp variant allelemodifies the risk-lowering effect of diuretics on myocardial infarction (MI). DESIGN, SETTING AND PARTICIPANTS: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis wasused to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. RESULTS: The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantlylower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the alpha-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). CONCLUSION: This study suggests that the alpha-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.