P-125: Large conductance K+ channel B1 subunit polymorphisms affect human stress blood pressure responses

Repeated pressor responses may result in sustained hypertension in individuals at genetic risk /BK cs are large-conductance, voltage and Ca2+-sensitive potassium channels that are expressed in vascular smooth muscle cells and brain, controlling membrane repolarization in such excitable cells. The regulatory (β1) subunit of BK channels (KCNMB1) is perhaps the best-characterized non-genomic target of estrogen. Mice with disrupted β1 subunit of BK have increased blood pressure, and variants in BK β1 in humans alter heart rate variability and baroreflex function. We hypothesized that polymorphisms at KCNMB1 would influence stress blood pressure responses in humans, and their impact might differ in men and women. 31 pairs of twins (20 monozygotic [MZ], 11 dizygotic [DZ]) and 75 sibs of twins (n=138 individuals) were studied. BP and HR were recorded with a calibrated radial artery applanation device and dedicated software during the cold pressor test (CPT; immersion of non-dominant hand in ice water for 1 minute). 6 common SNPs in KCNMB1 were chosen: C-339T and A-94C in the promoter, C74T and C339T in exon1, A440T in intron A, A4445G in intron B, and Lys65Glu (A5843G) in Exon 3. Heritability estimates (from twin correlations) for CPT were 0.23 for ΔSBP, 0.29 for ΔDBP and 0.43 for ΔHR. C339T showed an association with DHR (P=0.01), pre-CPT HR (P=0.007) and ΔDBP (P=0.057). A4445G showed a strong association with post-CPT SBP (P=0.01) and some association with ΔSBP, ΔDBP and post DBP (P=0.07–0.08). Lys65Glu showed an association with post-CPT HR only (P=0.03). 3 remaining SNPs showed no associations. Significant modification by gender was found for C339T and post SBP (P=0.05), A4445G) and ΔDBP (P=0.05), C-339T and ΔDBP (P=0.04), C74T and pre-CPT DBP (P=0.08). Haplotypes across the 6 SNPs were generated using MLOCUS, but no significant associations were found. We conclude that pressor responses to environmental stress are heritable, and suggest that variability in such responses is predicted by allelic variation at certain positions in KCNMB1. Further work will be performed in larger numbers of twins and siblings in order to better characterize the involvement of KCNMB1 genetic variation in stress blood pressure responses, and the possible mediation of gender differences in stress responses by such variants. Am J Hypertens (2004) 17, 78A–78A; doi: 10.1016/j.amjhyper.2004.03.199