Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 2, Issue 4, Pages 362-U136Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.109.857839
Keywords
genetics; pharmacology; ion channels; calcium; pharmacogenetics
Funding
- NIH [HL074730, GM074492, RR017568]
- University of Florida
- Abbott Laboratories [K23HL91120]
- Baxter
- Bioheart
- Cardium
- Pfizer
- Viron
- Abbott
- Berlex Lab/Bayer HealthCare
- Astra Zeneca
- Boehringer Ingelheim
- CV Therapeutics
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Background-The gene encoding the target of calcium channel blockers, the alpha 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 beta-blocker therapy, and a third group in which calcium channel blocker and beta-blocker therapy are equivalent. (Circ Cardiovasc Genet. 2009; 2: 362-370.)
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