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Objective: 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 [beta]1 regulatory subunit of the Ca2 -dependent potassium channel modulates the risk of diastolic hypertension in humans.

Methods: We have studied polymorphisms in the pore-forming [alpha] subunit gene (KCNMA1) and their association to hypertension and myocardial infarction.

Results: 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.

Conclusion: 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.

(C) 2008 Lippincott Williams & Wilkins, Inc.