Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry

Marguerite R. Irvin; Colleen M. Sitlani; Raymond Noordam; Christie L. Avery; Joshua C. Bis; James S. Floyd; Jin Li; Nita A. Limdi; Vinodh Srinivasasainagendra; James Stewart; Renée de Mutsert; Dennis O. Mook-Kanamori; Leonard Lipovich; Erica L. Kleinbrink; Albert Smith; Traci M. Bartz; Eric A. Whitsel; Andre G. Uitterlinden; Kerri L. Wiggins; James G. Wilson; Degui Zhi; Bruno H. Stricker; Jerome I. Rotter; Donna K. Arnett; Bruce M. Psaty; Leslie A. Lange

doi:10.1038/s41397-018-0021-9

Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry

Marguerite R. Irvin, Colleen M. Sitlani, Raymond Noordam, Christie L. Avery, Joshua C. Bis, James S. Floyd, Jin Li, Nita A. Limdi, Vinodh Srinivasasainagendra, James Stewart, Renée de Mutsert, Dennis O. Mook-Kanamori, Leonard Lipovich, Erica L. Kleinbrink, Albert Smith, Traci M. Bartz, Eric A. Whitsel, Andre G. Uitterlinden, Kerri L. Wiggins, James G. WilsonDegui Zhi, Bruno H. Stricker, Jerome I. Rotter, Donna K. Arnett, Bruce M. Psaty, Leslie A. Lange

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

2 Scopus citations

Abstract

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10 ⁻⁸ ) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10 ⁻⁸ ; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

Original language	English
Pages (from-to)	97-108
Number of pages	12
Journal	Pharmacogenomics Journal
Volume	19
Issue number	1
DOIs	https://doi.org/10.1038/s41397-018-0021-9
State	Published - Feb 1 2019

Bibliographical note

Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.

Funding

Jackson Heart Study: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201 300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Rotterdam Study: The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by The Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Project No. 050-060-810. This collaborative effort was supported by an award from the National Heart, Lung and Blood Institute (R01-HL-103612, PI BMP). NEO Study: The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). Heart and Vascular Health Studies: The Heart and Vascular Health Studies has been funded in part by NHLBI grants R01HL085251 and R01HL073410. Atherosclerosis Risk in Communities Study: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN26 8201100006C, HHSN268201100007C, HHSN2682011000 08C, HHSN268201100009C, HHSN268201100010C, HH SN268201100011C, and HHSN268201100012C), R01HL0 87641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625 226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. HyperGEN: Genetics of Left Ventricular Hypertrophy: The HyperGEN: Genetics of Left Ventricular Hypertrophy is ancillary to the Family Blood Pressure Program, http:// clinicaltrials.gov/ct/show/NCT00005267. Funding sources included National Heart, Lung, and Blood Institute grant R01HL055673 and cooperative agreements (U01) with the National Heart, Lung, and Blood Institute: U01HL054471, U01HL54515 (UT); U01HL054472, U01HL054496 (MN); U01HL054473 (DCC); U01HL054495 (AL); U01HL05 4509 (NC). AGES: Age, Gene, Environment, Susceptibility—Reykjavik Study: This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. Funding Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN2682008 00007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01 HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Funders	Funder number
Centre National de Génotypage
Dutch Science Organization	916.14.023
Netherlands Genomics Initiative	050-060-810
Research Institute for Diseases in the Elderly
Southern California Diabetes Endocrinology Research Center
National Institutes of Health (NIH)	U01HL05 4509, N01-AG-1-2100, U01HL54515, 271201200022C, U01, UL1RR025005
National Institutes of Health (NIH)
National Institute on Aging
National Heart, Lung, and Blood Institute (NHLBI)	R01HL0 87641, R01HL073410, R01HL130114, N01HC85081, U01HL080295, N01HC85082, R01HL105756, N01HC85080, N01HC85086, N01HC85083, HHSN268201100009C, HHSN2682008 00007C, U01HL054496, U01HL054473, U01HL054495, U01HL054472, U01HL054471, R01HL086694, R01HL055673, R01 HL120393, N01HC55222, R01HL59367, R01-HL-103612, N01HC85079, R01HL085251, R01HL087652
National Heart, Lung, and Blood Institute (NHLBI)
National Human Genome Research Institute	U01HG004402
National Human Genome Research Institute
National Institute of Diabetes and Digestive and Kidney Diseases
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01AG023629
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
National Center for Advancing Translational Sciences (NCATS)	UL1TR000124
National Center for Advancing Translational Sciences (NCATS)
National Institute on Minority Health and Health Disparities (NIMHD)
Indiana Clinical and Translational Sciences Institute
Diabetes Research Connection	DK063491
Diabetes Research Connection
European Commission
Universiteit Leiden
ZonMw Memorabel
Erasmus Universiteit Rotterdam
Hartstichting
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Ministerie van Onderwijs, Cultuur en Wetenschap
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	911.03.012, 175.010.2005.011
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Leids Universitair Medisch Centrum
Hjartavernd

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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10.1038/s41397-018-0021-9

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Irvin, M. R., Sitlani, C. M., Noordam, R., Avery, C. L., Bis, J. C., Floyd, J. S., Li, J., Limdi, N. A., Srinivasasainagendra, V., Stewart, J., de Mutsert, R., Mook-Kanamori, D. O., Lipovich, L., Kleinbrink, E. L., Smith, A., Bartz, T. M., Whitsel, E. A., Uitterlinden, A. G., Wiggins, K. L., ... Lange, L. A. (2019). Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. Pharmacogenomics Journal, 19(1), 97-108. https://doi.org/10.1038/s41397-018-0021-9

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title = "Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry",

abstract = " We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10 −8 ) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10 −8 ; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.",

author = "Irvin, \{Marguerite R.\} and Sitlani, \{Colleen M.\} and Raymond Noordam and Avery, \{Christie L.\} and Bis, \{Joshua C.\} and Floyd, \{James S.\} and Jin Li and Limdi, \{Nita A.\} and Vinodh Srinivasasainagendra and James Stewart and \{de Mutsert\}, Ren{\'e}e and Mook-Kanamori, \{Dennis O.\} and Leonard Lipovich and Kleinbrink, \{Erica L.\} and Albert Smith and Bartz, \{Traci M.\} and Whitsel, \{Eric A.\} and Uitterlinden, \{Andre G.\} and Wiggins, \{Kerri L.\} and Wilson, \{James G.\} and Degui Zhi and Stricker, \{Bruno H.\} and Rotter, \{Jerome I.\} and Arnett, \{Donna K.\} and Psaty, \{Bruce M.\} and Lange, \{Leslie A.\}",

note = "Publisher Copyright: {\textcopyright} 2018, Macmillan Publishers Limited, part of Springer Nature.",

year = "2019",

month = feb,

day = "1",

doi = "10.1038/s41397-018-0021-9",

language = "English",

volume = "19",

pages = "97--108",

number = "1",

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Irvin, MR, Sitlani, CM, Noordam, R, Avery, CL, Bis, JC, Floyd, JS, Li, J, Limdi, NA, Srinivasasainagendra, V, Stewart, J, de Mutsert, R, Mook-Kanamori, DO, Lipovich, L, Kleinbrink, EL, Smith, A, Bartz, TM, Whitsel, EA, Uitterlinden, AG, Wiggins, KL, Wilson, JG, Zhi, D, Stricker, BH, Rotter, JI, Arnett, DK, Psaty, BM & Lange, LA 2019, 'Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry', Pharmacogenomics Journal, vol. 19, no. 1, pp. 97-108. https://doi.org/10.1038/s41397-018-0021-9

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T1 - Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry

AU - Irvin, Marguerite R.

AU - Sitlani, Colleen M.

AU - Noordam, Raymond

AU - Avery, Christie L.

AU - Bis, Joshua C.

AU - Floyd, James S.

AU - Li, Jin

AU - Limdi, Nita A.

AU - Srinivasasainagendra, Vinodh

AU - Stewart, James

AU - de Mutsert, Renée

AU - Mook-Kanamori, Dennis O.

AU - Lipovich, Leonard

AU - Kleinbrink, Erica L.

AU - Smith, Albert

AU - Bartz, Traci M.

AU - Whitsel, Eric A.

AU - Uitterlinden, Andre G.

AU - Wiggins, Kerri L.

AU - Wilson, James G.

AU - Zhi, Degui

AU - Stricker, Bruno H.

AU - Rotter, Jerome I.

AU - Arnett, Donna K.

AU - Psaty, Bruce M.

AU - Lange, Leslie A.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10 −8 ) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10 −8 ; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

AB - We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10 −8 ) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10 −8 ; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

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Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry

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