CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response.
BACKGROUND
The gene encoding the target of calcium channel blockers, the alpha1c-subunit of the L-type calcium channel (CACNA1C), has not been well characterized, and only small pharmacogenetic studies testing this gene have been published to date.


RESULTS
Resequencing of CACNA1C was performed followed by a nested case-control study of the INternational VErapamil SR/trandolapril STudy (INVEST) GENEtic Substudy (INVEST-GENES). Of 46 polymorphisms identified, 8 were assessed in the INVEST-GENES. Rs1051375 was found to have a significant interaction with treatment strategy (P=0.0001). Rs1051375 A/A genotype was associated with a 46% reduction in the primary outcome among those randomized to verapamil SR treatment, when compared with atenolol treatment (odds ratio 0.54 95% CI 0.32 to 0.92). In heterozygous A/G individuals, there was no difference in the occurrence of the primary outcome when randomized to verapamil SR versus atenolol treatment (odds ratio 1.47 95% CI 0.86 to 2.53), whereas homozygous G/G individuals had a greater than 4-fold increased risk of the primary outcome with verapamil treatment compared with those randomized to atenolol treatment (odds ratio 4.59 95% CI 1.67 to 12.67). We did not identify allelic expression imbalance or differences in mRNA expression in heart tissue by rs1051375 genotype.


CONCLUSIONS
Variation in CACNA1C is associated with treatment response among hypertensive patients with stable coronary artery disease. Our data suggest a genetically defined group of patients that benefit most from calcium channel blocker therapy, a group that benefits most from beta-blocker therapy, and a third group in which calcium channel blocker and beta-blocker therapy are equivalent.
Beitelshees
Amber L
AL
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL, USA.
Navare
Hrishikesh
H
Wang
Danxin
D
Gong
Yan
Y
Wessel
Jennifer
J
Moss
James I
JI
Langaee
Taimour Y
TY
Cooper-DeHoff
Rhonda M
RM
Sadee
Wolfgang
W
Pepine
Carl J
CJ
Schork
Nicolas J
NJ
Johnson
Julie A
JA
D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001262:Atenolol / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D014700:Verapamil / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D001262:Atenolol; D014700:Verapamil