KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST).

Abstract

OBJECTIVES:

We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES).

BACKGROUND:

KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed.

METHODS:

Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed.

RESULTS:

Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype.

CONCLUSIONS:

Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes.

• Authors: Amber L Beitelshees, Yan Gong, Danxin Wang, Nicholas J Schork, Rhonda M Cooper-Dehoff, Taimour Y Langaee, Mark D Shriver, Wolfgang Sadee, Harm J Knot, Carl J Pepine, Julie A Johnson, INVEST Investigators
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 17 Issue 9 Pg. 719-29 (Sep 2007) ISSN: 1744-6872 [Print] United States
• PMID: 17700361 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Calcium Channel Blockers
• DNA Primers
• Indoles
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits
• trandolapril
• Verapamil

Topics

• Aged
• Antihypertensive Agents (adverse effects, therapeutic use)
• Base Sequence
• Calcium Channel Blockers (adverse effects, therapeutic use)
• DNA Primers (genetics)
• Female
• Genotype
• Humans
• Hypertension (drug therapy, genetics, metabolism)
• Indoles (adverse effects, therapeutic use)
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits (genetics)
• Male
• Middle Aged
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Verapamil (adverse effects, therapeutic use)