Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

Caitrin W. McDonough; Helen R. Warren; John R. Jack; Alison A. Motsinger-Reif; Nicole D. Armstrong; Joshua C. Bis; John S. House; Sonal Singh; Nihal M. El Rouby; Yan Gong; Joesyf C. Mychaleckyj; Daniel M. Rotroff; Oscar R. Benavente; Mark J. Caulfield; Alessandrio Doria; Carl J. Pepine; Bruce M. Psaty; Valeria Glorioso; Nicola Glorioso; Timo P. Hiltunen; Kimmo K. Kontula; Donna K. Arnett; John B. Buse; Marguerite R. Irvin; Julie A. Johnson; Patricia B. Munroe; Michael J. Wagner; Rhonda M. Cooper-DeHoff

doi:10.1002/cpt.2355

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

Caitrin W. McDonough, Helen R. Warren, John R. Jack, Alison A. Motsinger-Reif, Nicole D. Armstrong, Joshua C. Bis, John S. House, Sonal Singh, Nihal M. El Rouby, Yan Gong, Joesyf C. Mychaleckyj, Daniel M. Rotroff, Oscar R. Benavente, Mark J. Caulfield, Alessandrio Doria, Carl J. Pepine, Bruce M. Psaty, Valeria Glorioso, Nicola Glorioso, Timo P. HiltunenKimmo K. Kontula, Donna K. Arnett, John B. Buse, Marguerite R. Irvin, Julie A. Johnson, Patricia B. Munroe, Michael J. Wagner, Rhonda M. Cooper-DeHoff

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10⁻⁸). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10⁻⁴, Beta = 3.09, diastolic BP response P = 5 × 10⁻³, Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10⁻⁴, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

Original language	English
Pages (from-to)	723-732
Number of pages	10
Journal	Clinical Pharmacology and Therapeutics
Volume	110
Issue number	3
DOIs	https://doi.org/10.1002/cpt.2355
State	Published - Sep 2021

Bibliographical note

Funding Information:
C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome-wide genotyping for INVEST-GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492-05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496. Both the PEAR and PEAR-2 studies were supported by NIH grants U01-GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE-Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB-SS studies were supported by the HYPERGENES project (FP7-HEALTHF4-2007-201550), InterOmics (PB05 MIUR-CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457.

Funding Information:
C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01‐HC‐95178, N01‐HC‐95179, N01‐HC‐95180, N01‐HC‐95181, N01‐HC‐95182, N01‐HC‐95183, N01‐HC‐95184, IAA #Y1‐HC‐9035, and IAA #Y1‐HC‐1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome‐wide genotyping for INVEST‐GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492‐05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496 . Both the PEAR and PEAR‐2 studies were supported by NIH grants U01‐GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE‐Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB‐SS studies were supported by the HYPERGENES project (FP7‐HEALTHF4‐2007‐201550), InterOmics (PB05 MIUR‐CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457.

Publisher Copyright:
© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

Access to Document

10.1002/cpt.2355

Cite this

McDonough, C. W., Warren, H. R., Jack, J. R., Motsinger-Reif, A. A., Armstrong, N. D., Bis, J. C., House, J. S., Singh, S., El Rouby, N. M., Gong, Y., Mychaleckyj, J. C., Rotroff, D. M., Benavente, O. R., Caulfield, M. J., Doria, A., Pepine, C. J., Psaty, B. M., Glorioso, V., Glorioso, N., ... Cooper-DeHoff, R. M. (2021). Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies. Clinical Pharmacology and Therapeutics, 110(3), 723-732. https://doi.org/10.1002/cpt.2355

@article{01aeaf2d91cd4ec38658a9f03797838b,

title = "Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies",

abstract = "We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients{\textquoteright} subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.",

author = "McDonough, {Caitrin W.} and Warren, {Helen R.} and Jack, {John R.} and Motsinger-Reif, {Alison A.} and Armstrong, {Nicole D.} and Bis, {Joshua C.} and House, {John S.} and Sonal Singh and {El Rouby}, {Nihal M.} and Yan Gong and Mychaleckyj, {Joesyf C.} and Rotroff, {Daniel M.} and Benavente, {Oscar R.} and Caulfield, {Mark J.} and Alessandrio Doria and Pepine, {Carl J.} and Psaty, {Bruce M.} and Valeria Glorioso and Nicola Glorioso and Hiltunen, {Timo P.} and Kontula, {Kimmo K.} and Arnett, {Donna K.} and Buse, {John B.} and Irvin, {Marguerite R.} and Johnson, {Julie A.} and Munroe, {Patricia B.} and Wagner, {Michael J.} and Cooper-DeHoff, {Rhonda M.}",

note = "Funding Information: C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome-wide genotyping for INVEST-GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492-05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496. Both the PEAR and PEAR-2 studies were supported by NIH grants U01-GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE-Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB-SS studies were supported by the HYPERGENES project (FP7-HEALTHF4-2007-201550), InterOmics (PB05 MIUR-CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457. Funding Information: C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01‐HC‐95178, N01‐HC‐95179, N01‐HC‐95180, N01‐HC‐95181, N01‐HC‐95182, N01‐HC‐95183, N01‐HC‐95184, IAA #Y1‐HC‐9035, and IAA #Y1‐HC‐1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome‐wide genotyping for INVEST‐GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492‐05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496 . Both the PEAR and PEAR‐2 studies were supported by NIH grants U01‐GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE‐Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB‐SS studies were supported by the HYPERGENES project (FP7‐HEALTHF4‐2007‐201550), InterOmics (PB05 MIUR‐CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457. Publisher Copyright: {\textcopyright} 2021 The Authors. Clinical Pharmacology & Therapeutics {\textcopyright} 2021 American Society for Clinical Pharmacology and Therapeutics",

year = "2021",

month = sep,

doi = "10.1002/cpt.2355",

language = "English",

volume = "110",

pages = "723--732",

number = "3",

}

McDonough, CW, Warren, HR, Jack, JR, Motsinger-Reif, AA, Armstrong, ND, Bis, JC, House, JS, Singh, S, El Rouby, NM, Gong, Y, Mychaleckyj, JC, Rotroff, DM, Benavente, OR, Caulfield, MJ, Doria, A, Pepine, CJ, Psaty, BM, Glorioso, V, Glorioso, N, Hiltunen, TP, Kontula, KK, Arnett, DK, Buse, JB, Irvin, MR, Johnson, JA, Munroe, PB, Wagner, MJ & Cooper-DeHoff, RM 2021, 'Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies', Clinical Pharmacology and Therapeutics, vol. 110, no. 3, pp. 723-732. https://doi.org/10.1002/cpt.2355

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies. / McDonough, Caitrin W.; Warren, Helen R.; Jack, John R. et al.
In: Clinical Pharmacology and Therapeutics, Vol. 110, No. 3, 09.2021, p. 723-732.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Adverse Cardiovascular Outcomes and Antihypertensive Treatment

T2 - A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

AU - McDonough, Caitrin W.

AU - Warren, Helen R.

AU - Jack, John R.

AU - Motsinger-Reif, Alison A.

AU - Armstrong, Nicole D.

AU - Bis, Joshua C.

AU - House, John S.

AU - Singh, Sonal

AU - El Rouby, Nihal M.

AU - Gong, Yan

AU - Mychaleckyj, Joesyf C.

AU - Rotroff, Daniel M.

AU - Benavente, Oscar R.

AU - Caulfield, Mark J.

AU - Doria, Alessandrio

AU - Pepine, Carl J.

AU - Psaty, Bruce M.

AU - Glorioso, Valeria

AU - Glorioso, Nicola

AU - Hiltunen, Timo P.

AU - Kontula, Kimmo K.

AU - Arnett, Donna K.

AU - Buse, John B.

AU - Irvin, Marguerite R.

AU - Johnson, Julie A.

AU - Munroe, Patricia B.

AU - Wagner, Michael J.

AU - Cooper-DeHoff, Rhonda M.

N1 - Funding Information: C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome-wide genotyping for INVEST-GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492-05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496. Both the PEAR and PEAR-2 studies were supported by NIH grants U01-GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE-Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB-SS studies were supported by the HYPERGENES project (FP7-HEALTHF4-2007-201550), InterOmics (PB05 MIUR-CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457. Funding Information: C.W.M. is supported by National Institutes of Health (NIH) grant K01 HL141690. ASCOT was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Barts Biomedical Research Unit and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity, and the Medical Research Council through G952010. ACCORD research was supported by NIH grants R01 HL110380 and R01 HL110400, and intramural funds from the National Institute of Environmental Health Sciences. ACCORD cohort was supported by Contract Nos. N01‐HC‐95178, N01‐HC‐95179, N01‐HC‐95180, N01‐HC‐95181, N01‐HC‐95182, N01‐HC‐95183, N01‐HC‐95184, IAA #Y1‐HC‐9035, and IAA #Y1‐HC‐1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). INVEST was supported by the NIH grants R01 HL074730, U01 GM074492, and NIH CTSA grant UL1 RR092890, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. The genome‐wide genotyping for INVEST‐GENES was provided by RIKEN. SPS3 was supported by NIH grants R01 NS073346, U01 GM074492‐05S109, and U01 NS038529. Infrastructure for the CHARGE Consortium and the CHARGE Pharmacogenetics Working Group is supported in part by the NHLBI grants R01 HL105756, R01 HL103612, and R01 HL085251, and CHS contract number 75N92021D00006. Study descriptions and acknowledgements for the participating CHARGE cohorts are available in https://doi.org/10.1371/journal.pone.0140496 . Both the PEAR and PEAR‐2 studies were supported by NIH grants U01‐GM074492 and UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University), and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. LIFE‐Fin and GENRES were supported by the Sigrid Juselius Foundation, The Finnish Foundation for Cardiovascular Research, and the Helsinki University Central Hospital. BB‐SS studies were supported by the HYPERGENES project (FP7‐HEALTHF4‐2007‐201550), InterOmics (PB05 MIUR‐CNR Italian Flagship Project), and the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari—ONLUS.” GenHAT was supported by NIH grants R01 HL123782 and R01 HL063082, and N.A. was also supported by NIH grant T32 HL007457. Publisher Copyright: © 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics

PY - 2021/9

Y1 - 2021/9

N2 - We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

AB - We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients’ subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.

UR - http://www.scopus.com/inward/record.url?scp=85112363428&partnerID=8YFLogxK

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U2 - 10.1002/cpt.2355

DO - 10.1002/cpt.2355

M3 - Article

C2 - 34231218

AN - SCOPUS:85112363428

SN - 0009-9236

VL - 110

SP - 723

EP - 732

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 3

ER -

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

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