title: KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST).
abstract: OBJECTIVE
  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: Department of Pharmacy Practice, University of Florida, College of Pharmacy, Gainesville, USA.
authors: Amber L
authors: AL
authors: Beitelshees
authors: Yan
authors: Y
authors: Gong
authors: Danxin
authors: D
authors: Wang
authors: Nicholas J
authors: NJ
authors: Schork
authors: Rhonda M
authors: RM
authors: Cooper-Dehoff
authors: Taimour Y
authors: TY
authors: Langaee
authors: Mark D
authors: MD
authors: Shriver
authors: Wolfgang
authors: W
authors: Sadee
authors: Harm J
authors: HJ
authors: Knot
authors: Carl J
authors: CJ
authors: Pepine
authors: Julie A
authors: JA
authors: Johnson
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D014700:Verapamil / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017931:DNA Primers; D007211:Indoles; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; C052035:trandolapril; D014700:Verapamil
references: J Am Coll Cardiol. 2006 Feb 7;47(3):547-51
references: 16458134
references: Circ Res. 2005 Dec 9;97(12):1360-5
references: 16293791
references: J Biol Chem. 2005 Sep 23;280(38):32618-24
references: 16046395
references: Hum Genomics. 2005 Jun;2(2):81-9
references: 16004724
references: Pharmacol Ther. 2005 Apr;106(1):19-38
references: 15781120
references: J Pharmacol Exp Ther. 2004 Dec;311(3):1088-96
references: 15282265
references: J Am Coll Cardiol. 1998 Nov;32(5):1228-37
references: 9809930
references: Arch Intern Med. 1997 Nov 24;157(21):2413-46
references: 9385294
references: Nature. 2000 Oct 19;407(6806):870-6
references: 11057658
references: Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R255-60
references: 15358732
references: J Clin Invest. 2004 Apr;113(7):1032-9
references: 15057310
references: JAMA. 2003 Dec 3;290(21):2805-16
references: 14657064
references: Hum Genet. 2003 Jul;113(2):149-53
references: 12728311
references: Mol Biol Evol. 2002 Nov;19(11):1991-2004
references: 12411608
references: Pharmacotherapy. 2002 Aug;22(8):954-60
references: 12173798
references: J Hypertens. 2002 May;20(5):927-33
references: 12011654
references: Genome Res. 2001 Jan;11(1):163-9
references: 11156625
references: J Clin Pharmacol. 2000 Dec;40(12 Pt 2):1480-7
references: 11185670
references: Circ Res. 2000 Nov 24;87(11):E53-60
references: 11090555