Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers
BackgroundFor 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 H...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2018-03-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.117.006463 |
| _version_ | 1819178763549671424 |
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| author | Mohamed H. Shahin Daniela J. Conrado Daniel Gonzalez Yan Gong Maximilian T. Lobmeyer Amber L. Beitelshees Eric Boerwinkle John G. Gums Arlene Chapman Stephen T. Turner Rhonda M. Cooper‐DeHoff Julie A. Johnson |
| author_facet | Mohamed H. Shahin Daniela J. Conrado Daniel Gonzalez Yan Gong Maximilian T. Lobmeyer Amber L. Beitelshees Eric Boerwinkle John G. Gums Arlene Chapman Stephen T. Turner Rhonda M. Cooper‐DeHoff Julie A. Johnson |
| author_sort | Mohamed H. Shahin |
| collection | DOAJ |
| description | BackgroundFor 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 ResultsWe 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 genome‐wide 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. ConclusionsThis study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519. |
| first_indexed | 2024-12-22T21:47:43Z |
| format | Article |
| id | doaj.art-001adab1a66e4cd1997bf5b9453bb508 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-22T21:47:43Z |
| publishDate | 2018-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-001adab1a66e4cd1997bf5b9453bb5082022-12-21T18:11:27ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802018-03-017510.1161/JAHA.117.006463Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐BlockersMohamed H. Shahin0Daniela J. Conrado1Daniel Gonzalez2Yan Gong3Maximilian T. Lobmeyer4Amber L. Beitelshees5Eric Boerwinkle6John G. Gums7Arlene Chapman8Stephen T. Turner9Rhonda M. Cooper‐DeHoff10Julie A. Johnson11Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLDepartment of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FLDivision of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina, Chapel Hill, NCDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLDepartment of Medicine, University of Maryland, Baltimore, MDHuman Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TXDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLDepartment of Medicine, The University of Chicago, ILDivision of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MNDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FLBackgroundFor 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 ResultsWe 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 genome‐wide 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. ConclusionsThis study highlights OR10P1 and SNX9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.https://www.ahajournals.org/doi/10.1161/JAHA.117.006463atenololheart ratemetoprololpharmacogenomicsβ‐blockers |
| spellingShingle | Mohamed H. Shahin Daniela J. Conrado Daniel Gonzalez Yan Gong Maximilian T. Lobmeyer Amber L. Beitelshees Eric Boerwinkle John G. Gums Arlene Chapman Stephen T. Turner Rhonda M. Cooper‐DeHoff Julie A. Johnson Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atenolol heart rate metoprolol pharmacogenomics β‐blockers |
| title | Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers |
| title_full | Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers |
| title_fullStr | Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers |
| title_full_unstemmed | Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers |
| title_short | Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers |
| title_sort | genome wide association approach identified novel genetic predictors of heart rate response to β blockers |
| topic | atenolol heart rate metoprolol pharmacogenomics β‐blockers |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.117.006463 |
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