title: Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes.
abstract: We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Ben
authors.initials: B
authors.lastname: Burkley
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005165:Factor V / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D007211:Indoles / Q000493:pharmacokinetics*; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D019087:Selectins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: C048566:A1BG protein, human; D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D006023:Glycoproteins; D007136:Immunoglobulins; D007211:Indoles; D037102:Lectins; D008565:Membrane Proteins; C432400:SIGLEC12 protein, human; D019087:Selectins; C052035:trandolapril; D005165:Factor V; D004247:DNA; D014700:Verapamil
keywords: antihypertensive agents; calcium channel blockers; genetic variation; hypertension; pharmacogenetics; β-blockers