Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects
Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide. Gen...
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| Vydané v: | Circulation (New York, N.Y.) Ročník 140; číslo 4; s. 270 |
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| Hlavní autori: | , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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23.07.2019
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| ISSN: | 1524-4539, 1524-4539 |
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| Abstract | Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.
Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.
Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).
Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation. |
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| AbstractList | Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.
Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.
Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).
Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation. Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.BACKGROUNDDrug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.METHODSGenetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).RESULTSSuitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.CONCLUSIONSGenetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation. |
| Author | Jiang, Lan Feng, Qiping Elliott, Paul Gill, Dipender Georgakis, Marios K Wei, Wei-Qi Koskeridis, Fotios Evangelou, Evangelos Dichgans, Martin Malik, Rainer Dehghan, Abbas Tzoulaki, Ioanna Theodoratou, Evropi Denny, Joshua C |
| Author_xml | – sequence: 1 givenname: Dipender surname: Gill fullname: Gill, Dipender organization: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (D.G., P.E., E.E., A.D., I.T.) – sequence: 2 givenname: Marios K surname: Georgakis fullname: Georgakis, Marios K organization: Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany – sequence: 3 givenname: Fotios surname: Koskeridis fullname: Koskeridis, Fotios organization: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Greece (F.K., E.E., I.T.) – sequence: 4 givenname: Lan surname: Jiang fullname: Jiang, Lan organization: Division of Clinical Pharmacology, Department of Medicine (L.J., Q.F.), Vanderbilt University Medical Center, Nashville, TN – sequence: 5 givenname: Qiping surname: Feng fullname: Feng, Qiping organization: Division of Clinical Pharmacology, Department of Medicine (L.J., Q.F.), Vanderbilt University Medical Center, Nashville, TN – sequence: 6 givenname: Wei-Qi surname: Wei fullname: Wei, Wei-Qi organization: Department of Biomedical Informatics (W.-Q.W., J.C.D.), Vanderbilt University Medical Center, Nashville, TN – sequence: 7 givenname: Evropi surname: Theodoratou fullname: Theodoratou, Evropi organization: Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (E.T.) – sequence: 8 givenname: Paul surname: Elliott fullname: Elliott, Paul organization: Health Data Research UK-London (P.E.) – sequence: 9 givenname: Joshua C surname: Denny fullname: Denny, Joshua C organization: Department of Biomedical Informatics (W.-Q.W., J.C.D.), Vanderbilt University Medical Center, Nashville, TN – sequence: 10 givenname: Rainer surname: Malik fullname: Malik, Rainer organization: Institute for Stroke and Dementia Research, University Hospital (M.K.G., R.M., M.D.), Ludwig-Maximilians-Universität LMU, Munich, Germany – sequence: 11 givenname: Evangelos surname: Evangelou fullname: Evangelou, Evangelos organization: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Greece (F.K., E.E., I.T.) – sequence: 12 givenname: Abbas surname: Dehghan fullname: Dehghan, Abbas organization: UK Dementia Research Institute at Imperial College London, UK (P.E., A.D., I.T.) – sequence: 13 givenname: Martin surname: Dichgans fullname: Dichgans, Martin organization: German Center for Neurodegenerative Diseases (DZNE, Munich), Germany (M.D.) – sequence: 14 givenname: Ioanna surname: Tzoulaki fullname: Tzoulaki, Ioanna organization: UK Dementia Research Institute at Imperial College London, UK (P.E., A.D., I.T.) |
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