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The large conductance Ca2+-dependent potassium channel plays a critical role in the control of vascular tone, coupling local increases in intracellular Ca2+ to membrane hyperpolarization and vascular relaxation. It also impacts blood pressure by modulating the renin–angiotensin–aldosterone system. Previous studies have shown that a polymorphism in the β1 regulatory subunit of the Ca2+-dependent potassium channel modulates the risk of diastolic hypertension in humans.We have studied polymorphisms in the pore-forming α subunit gene (KCNMA1) and their association to hypertension and myocardial infarction.Sequencing of the KCNMA1 gene revealed two genetic variants (polymorphisms C864T and IVS17) in population-based epidemiological studies (4786 participants). We detected a significant increase in the frequency of the IVS17+37T>C polymorphism with severe systolic hypertension (48.3% for normotensive vs. 69% for severe systolic hypertension, P = 0.03) and with severe general hypertension (48.7 vs. 65.8%, P = 0.04), although the adjusted odd ratios did not reach statistical significance. Four C864T/IVS17 haplotypes were identified. Haplotype 4 (encompassing the C allele of the IVS17 polymorphism and the T allele of the C864T polymorphism) was related with increased severity of systolic and general hypertension as well as increased risk of myocardial infarction.Our study provides genetic evidence that highlights the relevance of the Ca2+-dependent potassium channel in the control of human blood pressure and its impact on cardiovascular disease.