Variable blood pressure response to verapamil by KCNMB1 genotype

Background The gain-of-function Glu65Lys mutation in the KCNMB1 potassium channel subunit was found protective against diastolic HTN in a Spanish population and Val110Leu has been associated with baroreflex function. We sought to determine whether Glu65Lys or Val110Leu were associated with variable verapamil response in a substudy of the INVEST trial. Methods Genetic samples were obtained from 611 (170 untreated and 441 stable background therapy) INVEST patients in whom the addition of verapamil was the only change to their antihypertensive treatment (Tx). Codons 65 and 110 were genotyped by pyrosequencing. The GLM procedure, controlling for age, BMI, baseline BP/heart rate (HR), and race was used to compare BP/HR response to verapamil at 6 weeks by genotype. Results Minor allele frequencies were 0.12 and 0.09 for codon 65 and 110, respectively. No differences in BP or HR response to verapamil were present by genotype in the entire population. However, when compared only in patients untreated at baseline, codon 65 and 110 variant allele carriers experienced significantly greater SBP reductions to verapamil at 6 weeks than non-variant allele carriers. (See Table). Conclusion Our data suggest that codon 65 and 110 genotype may be important determinants of variable SBP response to verapamil monotherapy. Our data also suggest that background antihypertensive therapy may confound or influence pharmacogenetic associations. Clinical Pharmacology & Therapeutics (2005) 77, P97–P97; doi: 10.1016/j.clpt.2004.12.263 Table 1.  Codon 65 genotype Tx SBP Tx HR Codon 110 genotype Tx SBP Tx HR Estimated adjusted means (95confidence intervals). * p=0.022. ** p=0.041. † p=0.098. Glu65Glu 140 (137, 142) 74 (72, 75) Val110Val 139 (137, 142) 75 (74, 76) Lys65 carrier 130 (122, 138)* 72 (68, 77) Leu110 carrier 130 (122, 139)** 71 (67, 75)†