Gene variants at loci related to blood pressure account for variation in response to antihypertensive drugs between black and white individuals

Iniesta, R. et al. (2019) Gene variants at loci related to blood pressure account for variation in response to antihypertensive drugs between black and white individuals. Hypertension, 74(3), pp. 614-622. (doi:10.1161/hypertensionaha.118.12177) (PMID:31327267)

Iniesta, R. et al. (2019) Gene variants at loci related to blood pressure account for variation in response to antihypertensive drugs between black and white individuals. Hypertension, 74(3), pp. 614-622. (doi:10.1161/hypertensionaha.118.12177) (PMID:31327267)

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Abstract

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (−3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Item Type:Articles
Additional Information:Sources of Funding: This work was performed as part of the Ancestry and biological Informative Markers in stratification of HYpertension stratified medicines programme in hypertension funded by the Medical Research Council and The British Heart Foundation. We also acknowledge support from the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre and Clinical Research Facility award to Guy’s and St Thomas′ NHS Foundation Trust in partnership with King’s College London, and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. PEAR and PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses) studies were 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). GenHAT (Genetics of Hypertension Associated Treatments) study was supported by National Institutes of Health (NIH) Heart, Lung, and Blood Institute grant 5 R01 HL-63082, Genetics of Hypertension Associated Treatment. The ALLHAT Trial (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was supported by a contract with the National Heart, Lung, and Blood Institute. GenHAT genotyping was funded by NIH Heart, Lung, and Blood Institute grant 1R01HL103612.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Campbell, Dr Desmond and Padmanabhan, Professor Sandosh
Authors: Iniesta, R., Campbell, D., Venturini, C., Faconti, L., Singh, S., Irvin, M. R., Cooper-DeHoff, R. M., Johnson, J. A., Turner, S. T., Arnett, D. K., Weale, M. E., Warren, H., Munroe, P. B., Cruickshank, K., Padmanabhan, S., Lewis, C., and Chowienczyk, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > MRC/CSO Unit
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:22 July 2019

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