CACNA1C gene polymorphisms, cardiovascular dz, tx response

Beitelshees AL, Navare H, Wang D, et al. CACNA1C gene polymorphisms, cardiovascular disease outcomes and treatment response. Circ Cardiovasc Genet 2009

doi: 10.1161/CIRCGENETICS.109.857839

http://circgenetics.ahajournals.org/cgi/content/abstract/CIRCGENETICS.109.857839v1
http://circgenetics.ahajournals.org/cgi/rapidpdf/CIRCGENETICS.109.857839v1

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Published Online
on June 3, 2009

Circulation: Cardiovascular Genetics. 2009
Published online before print June 3, 2009, doi: 10.1161/CIRCGENETICS.109.857839

Original Article
CACNA1C gene polymorphisms, cardiovascular disease outcomes and treatment response
Amber L. Beitelshees1; Hrishikesh Navare2; Danxin Wang3; Yan Gong2; Jennifer Wessel4; James Moss2; Taimour Y. Langaee2; Rhonda M. Cooper–DeHoff2; Wolfgang Sadee3; Carl J. Pepine4; Nicolas J. Schork5 and Julie A. Johnson2,6
1 University of Florida, Gainesville, FL & University of Maryland, Baltimore, MD;
2 University of Florida, Gainesville, FL;
3 The Ohio State University, Columbus, OH;
4 University of California at San Diego, La Jolla, CA;
5 The Scripps Translational Sciences Institute, La Jolla, CA
6 E-mail:

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, eight 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 compared to atenolol treatment (OR 0.54 95% CI 0.32-0.92). In heterozygous A/G individuals, there was no difference in the occurrence of the primary outcome when randomized to verapamil SR versus atenolol treatment (OR 1.47 95% CI 0.86-2.53), while homozygous G/G individuals had a greater than 4-fold increased risk of the primary outcome with verapamil treatment compared to those randomized to atenolol treatment (OR 4.59 95% CI 1.67-12.67). 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.

Key Words: calcium • genetics • ion channels • pharmacology • pharmacogenetics

Copyright © 2009 American Heart Association, Inc.