TY - JOUR
T1 - Genome-wide association approach identified novel genetic predictors of heart rate response to β-blockers
AU - Shahin, Mohamed H.
AU - Conrado, Daniela J.
AU - Gonzalez, Daniel
AU - Gong, Yan
AU - Lobmeyer, Maximilian T.
AU - Beitelshees, Amber L.
AU - Boerwinkle, Eric
AU - Gums, John G.
AU - Chapman, Arlene
AU - Turner, Stephen T.
AU - Cooper-DeHoff, Rhonda M.
AU - Johnson, Julie A.
N1 - Funding Information:
We appreciate the valuable contributions of the study participants of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2. We also would like to thank PEAR and PEAR-2 support staff and study physicians.PEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01 GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. Gonzalez receives support for research from the National Institute of Child Health and Human Development (K23HD083465) and the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org)
Funding Information:
PEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01 GM074492
Funding Information:
and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. Gonzalez receives support for research from the National Institute of Child Health and Human Development (K23HD083465) and the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org).
Publisher Copyright:
© 2018 The Authors.
PY - 2018/3/6
Y1 - 2018/3/6
N2 - Background--For many indications, the negative chronotropic effect of β-blockers is important to their efficacy, yet the heart rate (HR) response to β-blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to β-blockers. Methods and Results--We first performed 4 genome-wide association analyses for HR response to atenolol (a β1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta-analysis was then performed between the genomewide association analysis performed in PEAR atenolol monotherapy and add-on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P < 1E-05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1-adrenergic receptor blocker). From the genome-wide association meta-analyses, SNP rs17117817 near olfactory receptor family10 subfamily-p-member1 (OR10P1), and SNP rs2364349 in sorting nexin-9 (SNX9) replicated in blacks. The combined studies meta-analysis P values for the rs17117817 and rs2364349 reached genome-wide significance (rs17117817G-allele; Meta-β=5.53 beats per minute, Meta-P=2E-09 and rs2364349 A-allele; Meta-β=3.5 beats per minute, Meta-P=1E-08). Additionally, SNPs in the OR10P1 and SNX9 gene regions were also associated with HR response in whites. Conclusions--This study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to β-blockers.
AB - Background--For many indications, the negative chronotropic effect of β-blockers is important to their efficacy, yet the heart rate (HR) response to β-blockers varies. Herein, we sought to use a genome-wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to β-blockers. Methods and Results--We first performed 4 genome-wide association analyses for HR response to atenolol (a β1-adrenergic receptor blocker) as: (1) monotherapy or (2) add-on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta-analysis was then performed between the genomewide association analysis performed in PEAR atenolol monotherapy and add-on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P < 1E-05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1-adrenergic receptor blocker). From the genome-wide association meta-analyses, SNP rs17117817 near olfactory receptor family10 subfamily-p-member1 (OR10P1), and SNP rs2364349 in sorting nexin-9 (SNX9) replicated in blacks. The combined studies meta-analysis P values for the rs17117817 and rs2364349 reached genome-wide significance (rs17117817G-allele; Meta-β=5.53 beats per minute, Meta-P=2E-09 and rs2364349 A-allele; Meta-β=3.5 beats per minute, Meta-P=1E-08). Additionally, SNPs in the OR10P1 and SNX9 gene regions were also associated with HR response in whites. Conclusions--This study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to β-blockers.
KW - Atenolol
KW - Heart rate
KW - Metoprolol
KW - Pharmacogenomics
KW - β-blockers
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U2 - 10.1161/JAHA.117.006463
DO - 10.1161/JAHA.117.006463
M3 - Article
C2 - 29478026
AN - SCOPUS:85042699615
SN - 2047-9980
VL - 7
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 5
M1 - e006463
ER -