Edinburgh Research Explorer

Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects

Research output: Contribution to journalArticle

  • Dipender Gill
  • Marios K Georgakis
  • Fotios Koskeridis
  • Lan Jiang
  • QiPing Feng
  • Wei-Qi Wei
  • Evropi Theodoratou
  • Paul Elliott
  • Joshua C Denny
  • Rainer Malik
  • Evangelos Evangelou
  • Abbas Dehghan
  • Martin Dichgans
  • Ioanna Tzoulaki

Related Edinburgh Organisations

Open Access permissions

Open

Documents

  • Download as Adobe PDF

    Rights statement: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

    Final published version, 808 KB, PDF document

    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournalCirculation
Early online date25 Jun 2019
DOIs
Publication statusE-pub ahead of print - 25 Jun 2019

Abstract

BACKGROUND: 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.

METHODS: 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. 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.

RESULTS: 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).

CONCLUSIONS: 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.

ID: 89498018