CACNA1C Gene Polymorphisms, Cardiovascular Disease Outcomes, and Treatment Response

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 β-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent.

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease

“…5 On the basis of recent genome-wide association studies, calcium channels are implicated in the pathophysiology of BD, 18,19 and these channels also appear to be salient to CVD. 20,21 MDD and BD are the first and fourth most disabling conditions, respectively, among adolescents worldwide. 22 BD involves repeated episodes of mania/hypomania (elated or irritable mood together with other symptoms) that generally, but not always, alternate with episodes of depression (sadness or lack of interest/pleasure along with other symptoms).…”

Managing Hypertension in Patients with Diabetes

“…Other data from Beitelshees and colleagues suggests that polymorphisms in the CACNA1C gene may help identify groups that benefit most from calcium channel blocker therapy, a group that benefits from -blocker therapy, and a third group in which calcium channel blocker and -blocker therapy are equivalent [147]. Similar analyses leading to possible future predictions are available for -blocker treatment outcomes based on -adrenergic receptor gene polymorphisms [148], and promoter polymorphisms in angiotensinconverting enzyme [149].…”

Relationship between eNOS 894G>T Polymorphism and the Antihypertensive Efficiency of Two Dihydropyridine Calcium Channel Blocker Drugs, Azelnidipine and Nitrendipine, in Chinese EH Patients

“…The α1C subunit of the L-type calcium channel (CACNA1C) is involved in encoding the drug target of CCBs, the polymorphisms of which are widely recognized to be the most critical genetic factor of the response of dCCBs [10][11][12] . The key DHP-sensing residues of CACNA1C are defined in transmembrane segments IS6, IIIS5, IIIS6, IVS6 and the pore helix IIIP [5,13] .…”

“…As we known, the antihypertensive response rate of patients to dCCBs monotherapy is just a little above 50% in stage I or II hypertension patients; however, there are not reliable predictors to predict the hypotensive efficiency of dCCBs [5] . Previous researches have evidenced that gender is not an important factor to antihypertensive effect of CCBs when compared with age and initial BP; moreover, genetic factors can significantly influence the antihypertensive sensitivity of CCBs [6][7][8][9] .…”