Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES)

BACKGROUND: Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes. METHODS AND RESULTS: SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele. CONCLUSIONS: These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.