The KCNMB1 E65K variant is associated with reduced central pulse pressure in the community-based Framingham Offspring Cohort.
OBJECTIVE
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 beta1-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 (chi2, P > 0.05), and haplotype analysis found R2 = 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.


CONCLUSIONS
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.
Kelley-Hedgepeth
Alyson
A
aMCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, USA.
Peter
Inga
I
Montefusco
Maria Claudia
MC
Levy
Daniel
D
Benjamin
Emelia J
EJ
Vasan
Ramachandran S
RS
Mendelsohn
Michael E
ME
Housman
David
D
Huggins
Gordon S
GS
Mitchell
Gary F
GF
D000368:Aged; D001794:Blood Pressure; D001916:Brachial Artery / Q000033:anatomy & histology / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C531905:KCNMB1 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits