The KCNMB1 E65K variant is associated with reduced central pulse pressure in the community-based Framingham Offspring Cohort

Objectives: Genetic variants that influence large conductance calcium-activated potassium channel's function may alter arterial function and contribute to the known heritability of arterial stiffness and blood pressure. The β1-subunit (KCNMB1) of the large conductance calcium-activated potassium channel includes two coding region polymorphisms. E65K, a gain-of-function polymorphism, is predicted to enhance large conductance calcium-activated potassium channel opening and vasorelaxation, whereas V110L has no known effect. We and others have reported that E65K carriers have reduced blood pressure. Methods: To test our hypothesis that E65K has a favorable effect on arterial function, we related arterial tonometry and brachial artery phenotypes to genotypes in 1100 Framingham Offspring Study participants with available genotypes and phenotypes (53% women; mean age 61.5 ± 9.4 years). Results: The minor allele frequency was 0.10 for E65K and 0.09 for V110L; both were in Hardy-Weinberg equilibrium (χ, P > 0.05), and haplotype analysis found R = 0.01. E65K was associated with lower augmented pressure (7.4 ± 3.3 versus 9.0 ± 3.8 mmHg, P = 0.01) and central pulse pressure (47.1 ± 7.3 versus 50.7 ± 7.8 mmHg, P = 0.01) in multivariable analyses. No association was noted between E65K and mean arterial pressure, carotid-femoral pulse wave velocity or brachial artery diameter, flow velocity or volume flow. V110L was not associated with tonometry or brachial measures. Conclusion: A diminished augmented pressure in K-carriers suggests a reduced or delayed wave reflection and supports the hypothesis that E65K reduces arterial impedance mismatch in the arterial tree. Our findings in a middle-aged community-based cohort, if replicated, would support that E65K has a favorable effect on arterial function and pulsatile hemodynamic load.