Published online before print June 3, 2009, doi: 10.1161/CIRCGENETICS.109.857839
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Original Articles |
CACNA1C Gene Polymorphisms, Cardiovascular Disease Outcomes, and Treatment Response
From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (A.L.B., H.N., Y.G., J.M., T.Y.L., J.A.J.), University of Florida College of Pharmacy, Gainesville, Fla; Department of Pharmacology (D.W., W.S.), College of Medicine & Public Health, The Ohio State University, Columbus, Ohio; Department of Psychiatry (J.W., N.J.S.), University of California at San Diego, La Jolla, Calif; Division of Cardiology (R.M.C.D.H., C.J.P., J.A.J.), University of Florida College of Medicine, Mosville, Fla; The Scripps Translational Sciences Institute (N.J.S.), La Jolla, Calif; and Division of Endocrinology, Diabetes and Nutrition (A.L.B.), University of Maryland School of Medicine, Baltimore, Md. Dr. Beitelshees is now at the University of Maryland.
Correspondence to Dr. Julie A. Johnson, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, P.O. Box 100486, Gainesville, FL. E-mail johnson{at}cop.ufl.edu
Received July 11, 2008; accepted May 21, 2009.
Background— The gene encoding the target of calcium channel blockers, the 
1c-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.
Methods and 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 β-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent.
Key Words: genetics • pharmacology • ion channels • calcium • pharmacogenetics
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.857839/DC1.