Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes

McDonough, C.W., Gong, Y., Padmanabhan, S. , Burkley, B., Langaee, T.Y., Melander, O., Pepine, C.J., Dominiczak, A.F. , Cooper-DeHoff, R.M. and Johnson, J.A. (2013) Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes. Hypertension, 62(1), pp. 48-54. (doi:10.1161/HYPERTENSIONAHA.111.00823)

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Publisher's URL: http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00823

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: McDonough, C.W., Gong, Y., Padmanabhan, S., Burkley, B., Langaee, T.Y., Melander, O., Pepine, C.J., Dominiczak, A.F., Cooper-DeHoff, R.M., and Johnson, J.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
ISSN:0194-911X
ISSN (Online):1524-4563

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
239331BHF ChairAnna DominiczakBritish Heart Foundation (BHF)CH/98001RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
483571Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and "hypercontrols"Anna DominiczakBritish Heart Foundation (BHF)SP/08/005/25115RI CARDIOVASCULAR & MEDICAL SCIENCES
417951Hypertension pharmacogenetics - discovering genetics determinants of blood pressure responseSandosh PadmanabhanBritish Heart Foundation (BHF)FS/05/095/19937RI CARDIOVASCULAR & MEDICAL SCIENCES
534191Genetic dissection of hypertension - SNPs, sequence, Pathways to clinical translation.Sandosh PadmanabhanBritish Heart Foundation (BHF)FS/10/016/28162RI CARDIOVASCULAR & MEDICAL SCIENCES