title: Genetic variation in the beta2 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).
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Niu
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Heather M
authors.initials: HM
authors.lastname: Davis
authors.forename: Hazem
authors.initials: H
authors.lastname: Elewa
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: James I
authors.initials: JI
authors.lastname: Moss
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D005006:Ethnicity; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; C107597:CACNB2 protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D021122:Protein Subunits