Abstract 4414: DNA Variations in Voltage-gated Calcium Channel Beta 2 Subunit (CACNB2) Gene, Functional Consequences, and Association with Adverse Cardiovascular Outcomes in the INternational VErapamil SR-trandolapril STudy-GENEtic Substudy
Background: Genetic variations in the CACNB2 gene, which encodes a regulatory subunit of the L-type calcium channel, have not been thoroughly characterized. We undertook a single nucleotide polymorphism (SNP) discovery effort to characterize SNPs in CACNB2 and to determine if these SNPs were associated with adverse cardiovascular outcomes in patients with hypertension and coronary artery disease (CAD), and if associated, to determine functional underpinnings.
Methods: Genomic DNA from 60 ethnically diverse individuals was used for SNP discovery. SNPs from exons, intron/exon junctions, 5′ and 3′UTR of CACNB2 were identified and characterized by direct DNA sequencing. Four common SNPs (rs12764271, rs7069292, rs16917273, and rs2357928) from the 14 SNPs that were predicted to be functional by PolyMApr, were selected for a clinical association study in 1032 hypertensive CAD patients in INVEST-GENES who were randomized to atenolol or verapamil-SR-based treatment. Reporter assays were performed in CHO and HEK293 cells to assess the functional significance of the promoter SNP (rs2357928) showing clinical significance.
Results: 74 SNPs were identified, including 45 novel SNPs not in dbSNP. Low levels of linkage disequilibrium among the 74 SNPs was observed in all three race/ethnicity groups. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy on adverse cardiovascular outcomes (p for interaction =0.009). Variant A carriers had 2-fold higher risk for adverse cardiovascular outcomes compared to GG homozygous (odds ratio: 2.04, 95% CI: 1.09 – 3.83, p = 0.027) in the atenolol-based treatment strategy but not in verapamil SR-based calcium channel blocker treatment strategy (0.74, 0.44 – 1.22, p = 0.23). The analysis of reporter assay of this SNP in both CHO and HEK 293 cells showed a significant decrease in the expression of allele A compared to allele G (p=0.012), suggesting lower transcriptional activity for allele A. Conclusion Our data suggest a CACNB2 variant may play an important role in drug response in cardiovascular disease and risk of adverse cardiovascular outcomes.