CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response

Amber L. Beitelshees, Hrishikesh Navare, Danxin Wang, Yan Gong, Jennifer Wessel, James I. Moss, Taimour Y. Langaee, Rhonda M. Cooper-DeHoff, Wolfgang Sadee, Carl J. Pepine, Nicolas J. Schork, Julie A. Johnson

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Background-The gene encoding the target of calcium channel blockers, the α1c-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 =-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent.

Original languageEnglish (US)
Pages (from-to)362-370
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume2
Issue number4
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Keywords

  • Calcium
  • Genetics
  • Ion channels
  • Pharmacogenetics
  • Pharmacology

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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  • Cite this

    Beitelshees, A. L., Navare, H., Wang, D., Gong, Y., Wessel, J., Moss, J. I., Langaee, T. Y., Cooper-DeHoff, R. M., Sadee, W., Pepine, C. J., Schork, N. J., & Johnson, J. A. (2009). CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. Circulation: Cardiovascular Genetics, 2(4), 362-370. https://doi.org/10.1161/CIRCGENETICS.109.857839