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

34 Citations (Scopus)

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 2009
Externally publishedYes

Fingerprint

Cardiovascular Diseases
Verapamil
trandolapril
Genes
Atenolol
Calcium Channel Blockers
Therapeutics
Odds Ratio
Genotype
Allelic Imbalance
L-Type Calcium Channels
Group Psychotherapy
Case-Control Studies
Coronary Artery Disease
Messenger RNA

Keywords

  • Calcium
  • Genetics
  • Ion channels
  • Pharmacogenetics
  • Pharmacology

ASJC Scopus subject areas

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

Cite this

CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. / Beitelshees, Amber L.; Navare, Hrishikesh; Wang, Danxin; Gong, Yan; Wessel, Jennifer; Moss, James I.; Langaee, Taimour Y.; Cooper-DeHoff, Rhonda M.; Sadee, Wolfgang; Pepine, Carl J.; Schork, Nicolas J.; Johnson, Julie A.

In: Circulation: Cardiovascular Genetics, Vol. 2, No. 4, 08.2009, p. 362-370.

Research output: Contribution to journalArticle

Beitelshees, AL, Navare, H, Wang, D, Gong, Y, Wessel, J, Moss, JI, Langaee, TY, Cooper-DeHoff, RM, Sadee, W, Pepine, CJ, Schork, NJ & Johnson, JA 2009, 'CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response', Circulation: Cardiovascular Genetics, vol. 2, no. 4, pp. 362-370. https://doi.org/10.1161/CIRCGENETICS.109.857839
Beitelshees, Amber L. ; Navare, Hrishikesh ; Wang, Danxin ; Gong, Yan ; Wessel, Jennifer ; Moss, James I. ; Langaee, Taimour Y. ; Cooper-DeHoff, Rhonda M. ; Sadee, Wolfgang ; Pepine, Carl J. ; Schork, Nicolas J. ; Johnson, Julie A. / CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. In: Circulation: Cardiovascular Genetics. 2009 ; Vol. 2, No. 4. pp. 362-370.
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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.",
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AU - Wessel, Jennifer

AU - Moss, James I.

AU - Langaee, Taimour Y.

AU - Cooper-DeHoff, Rhonda M.

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N2 - 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.

AB - 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.

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