Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

A. A. Seyerle; C. M. Sitlani; R. Noordam; S. M. Gogarten; J. Li; X. Li; D. S. Evans; F. Sun; M. A. Laaksonen; A. Isaacs; K. Kristiansson; H. M. Highland; J. D. Stewart; T. B. Harris; S. Trompet; J. C. Bis; G. M. Peloso; J. A. Brody; L. Broer; E. L. Busch; Q. Duan; A. M. Stilp; C. J. O'Donnell; P. W. Macfarlane; J. S. Floyd; J. A. Kors; H. J. Lin; R. Li-Gao; T. Sofer; R. Mendez-Giraldez; S. R. Cummings; S. R. Heckbert; A. Hofman; I Ford; Y. Li; L. J. Launer; K. Porthan; C. Newton-Cheh; M. D. Napier; K. F. Kerr; A. P. Reiner; K. M. Rice; J. Roach; B. M. Buckley; E. Z. Soliman; R. de Mutsert; N. Sotoodehnia; A. G. Uitterlinden; K. E. North; C. R. Lee; V Gudnason; T. Sturmer; F. R. Rosendaal; K. D. Taylor; K. L. Wiggins; J. G. Wilson; Y-D Chen; R. C. Kaplan; K. Wilhelmsen; L. A. Cupples; V Salomaa; C. van Duijn; J. W. Jukema; Y. Liu; D. O. Mook-Kanamori; L. A. Lange; R. S. Vasan; A. Smith; B. H. Stricker; C. C. Laurie; J. Rotter; E. A. Whitsel; B. M. Psaty; C. L. Avery

doi:10.1038/tpj.2017.10

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

A. A. Seyerle^*, C. M. Sitlani, R. Noordam, S. M. Gogarten, J. Li, X. Li, D. S. Evans, F. Sun, M. A. Laaksonen, A. Isaacs, K. Kristiansson, H. M. Highland, J. D. Stewart, T. B. Harris, S. Trompet, J. C. Bis, G. M. Peloso, J. A. Brody, L. Broer, E. L. BuschQ. Duan, A. M. Stilp, C. J. O'Donnell, P. W. Macfarlane, J. S. Floyd, J. A. Kors, H. J. Lin, R. Li-Gao, T. Sofer, R. Mendez-Giraldez, S. R. Cummings, S. R. Heckbert, A. Hofman, I Ford, Y. Li, L. J. Launer, K. Porthan, C. Newton-Cheh, M. D. Napier, K. F. Kerr, A. P. Reiner, K. M. Rice, J. Roach, B. M. Buckley, E. Z. Soliman, R. de Mutsert, N. Sotoodehnia, A. G. Uitterlinden, K. E. North, C. R. Lee, V Gudnason, T. Sturmer, F. R. Rosendaal, K. D. Taylor, K. L. Wiggins, J. G. Wilson, Y-D Chen, R. C. Kaplan, K. Wilhelmsen, L. A. Cupples, V Salomaa, C. van Duijn, J. W. Jukema, Y. Liu, D. O. Mook-Kanamori, L. A. Lange, R. S. Vasan, A. Smith, B. H. Stricker, C. C. Laurie, J. Rotter, E. A. Whitsel, B. M. Psaty, C. L. Avery

^*Corresponding author for this work

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

Abstract

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P < 5 x 10(-8)), we found suggestive evidence (P < 5 x 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Original language	English
Pages (from-to)	215-226
Number of pages	12
Journal	Pharmacogenomics Journal
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/tpj.2017.10
Publication status	Published - 1 Mar 2018

Keywords

BLOOD-PRESSURE RESPONSE
INFLUENCING ANTIHYPERTENSIVE RESPONSE
GENE-ENVIRONMENT INTERACTIONS
WIDE ASSOCIATION
GENOMEWIDE ASSOCIATION
HYPERTENSIVE PATIENTS
CARDIOVASCULAR DRUGS
SELECTION BIAS
UNITED-STATES
VARIANTS

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Seyerle, A. A., Sitlani, C. M., Noordam, R., Gogarten, S. M., Li, J., Li, X., Evans, D. S., Sun, F., Laaksonen, M. A., Isaacs, A., Kristiansson, K., Highland, H. M., Stewart, J. D., Harris, T. B., Trompet, S., Bis, J. C., Peloso, G. M., Brody, J. A., Broer, L., ... Avery, C. L. (2018). Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. Pharmacogenomics Journal, 18(2), 215-226. https://doi.org/10.1038/tpj.2017.10

@article{42f02fd38fb945b5b341c4dfc6d593c8,

title = "Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology",

abstract = "Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P < 5 x 10(-8)), we found suggestive evidence (P < 5 x 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.",

keywords = "BLOOD-PRESSURE RESPONSE, INFLUENCING ANTIHYPERTENSIVE RESPONSE, GENE-ENVIRONMENT INTERACTIONS, WIDE ASSOCIATION, GENOMEWIDE ASSOCIATION, HYPERTENSIVE PATIENTS, CARDIOVASCULAR DRUGS, SELECTION BIAS, UNITED-STATES, VARIANTS",

author = "Seyerle, {A. A.} and Sitlani, {C. M.} and R. Noordam and Gogarten, {S. M.} and J. Li and X. Li and Evans, {D. S.} and F. Sun and Laaksonen, {M. A.} and A. Isaacs and K. Kristiansson and Highland, {H. M.} and Stewart, {J. D.} and Harris, {T. B.} and S. Trompet and Bis, {J. C.} and Peloso, {G. M.} and Brody, {J. A.} and L. Broer and Busch, {E. L.} and Q. Duan and Stilp, {A. M.} and O'Donnell, {C. J.} and Macfarlane, {P. W.} and Floyd, {J. S.} and Kors, {J. A.} and Lin, {H. J.} and R. Li-Gao and T. Sofer and R. Mendez-Giraldez and Cummings, {S. R.} and Heckbert, {S. R.} and A. Hofman and I Ford and Y. Li and Launer, {L. J.} and K. Porthan and C. Newton-Cheh and Napier, {M. D.} and Kerr, {K. F.} and Reiner, {A. P.} and Rice, {K. M.} and J. Roach and Buckley, {B. M.} and Soliman, {E. Z.} and {de Mutsert}, R. and N. Sotoodehnia and Uitterlinden, {A. G.} and North, {K. E.} and Lee, {C. R.} and V Gudnason and T. Sturmer and Rosendaal, {F. R.} and Taylor, {K. D.} and Wiggins, {K. L.} and Wilson, {J. G.} and Y-D Chen and Kaplan, {R. C.} and K. Wilhelmsen and Cupples, {L. A.} and V Salomaa and {van Duijn}, C. and Jukema, {J. W.} and Y. Liu and Mook-Kanamori, {D. O.} and Lange, {L. A.} and Vasan, {R. S.} and A. Smith and Stricker, {B. H.} and Laurie, {C. C.} and J. Rotter and Whitsel, {E. A.} and Psaty, {B. M.} and Avery, {C. L.}",

year = "2018",

month = mar,

day = "1",

doi = "10.1038/tpj.2017.10",

language = "English",

volume = "18",

pages = "215--226",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

publisher = "Springer",

number = "2",

}

Seyerle, AA, Sitlani, CM, Noordam, R, Gogarten, SM, Li, J, Li, X, Evans, DS, Sun, F, Laaksonen, MA, Isaacs, A, Kristiansson, K, Highland, HM, Stewart, JD, Harris, TB, Trompet, S, Bis, JC, Peloso, GM, Brody, JA, Broer, L, Busch, EL, Duan, Q, Stilp, AM, O'Donnell, CJ, Macfarlane, PW, Floyd, JS, Kors, JA, Lin, HJ, Li-Gao, R, Sofer, T, Mendez-Giraldez, R, Cummings, SR, Heckbert, SR, Hofman, A, Ford, I, Li, Y, Launer, LJ, Porthan, K, Newton-Cheh, C, Napier, MD, Kerr, KF, Reiner, AP, Rice, KM, Roach, J, Buckley, BM, Soliman, EZ, de Mutsert, R, Sotoodehnia, N, Uitterlinden, AG, North, KE, Lee, CR, Gudnason, V, Sturmer, T, Rosendaal, FR, Taylor, KD, Wiggins, KL, Wilson, JG, Chen, Y-D, Kaplan, RC, Wilhelmsen, K, Cupples, LA, Salomaa, V, van Duijn, C, Jukema, JW, Liu, Y, Mook-Kanamori, DO, Lange, LA, Vasan, RS, Smith, A, Stricker, BH, Laurie, CC, Rotter, J, Whitsel, EA, Psaty, BM & Avery, CL 2018, 'Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology', Pharmacogenomics Journal, vol. 18, no. 2, pp. 215-226. https://doi.org/10.1038/tpj.2017.10

TY - JOUR

T1 - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

AU - Seyerle, A. A.

AU - Sitlani, C. M.

AU - Noordam, R.

AU - Gogarten, S. M.

AU - Li, J.

AU - Li, X.

AU - Evans, D. S.

AU - Sun, F.

AU - Laaksonen, M. A.

AU - Isaacs, A.

AU - Kristiansson, K.

AU - Highland, H. M.

AU - Stewart, J. D.

AU - Harris, T. B.

AU - Trompet, S.

AU - Bis, J. C.

AU - Peloso, G. M.

AU - Brody, J. A.

AU - Broer, L.

AU - Busch, E. L.

AU - Duan, Q.

AU - Stilp, A. M.

AU - O'Donnell, C. J.

AU - Macfarlane, P. W.

AU - Floyd, J. S.

AU - Kors, J. A.

AU - Lin, H. J.

AU - Li-Gao, R.

AU - Sofer, T.

AU - Mendez-Giraldez, R.

AU - Cummings, S. R.

AU - Heckbert, S. R.

AU - Hofman, A.

AU - Ford, I

AU - Li, Y.

AU - Launer, L. J.

AU - Porthan, K.

AU - Newton-Cheh, C.

AU - Napier, M. D.

AU - Kerr, K. F.

AU - Reiner, A. P.

AU - Rice, K. M.

AU - Roach, J.

AU - Buckley, B. M.

AU - Soliman, E. Z.

AU - de Mutsert, R.

AU - Sotoodehnia, N.

AU - Uitterlinden, A. G.

AU - North, K. E.

AU - Lee, C. R.

AU - Gudnason, V

AU - Sturmer, T.

AU - Rosendaal, F. R.

AU - Taylor, K. D.

AU - Wiggins, K. L.

AU - Wilson, J. G.

AU - Chen, Y-D

AU - Kaplan, R. C.

AU - Wilhelmsen, K.

AU - Cupples, L. A.

AU - Salomaa, V

AU - van Duijn, C.

AU - Jukema, J. W.

AU - Liu, Y.

AU - Mook-Kanamori, D. O.

AU - Lange, L. A.

AU - Vasan, R. S.

AU - Smith, A.

AU - Stricker, B. H.

AU - Laurie, C. C.

AU - Rotter, J.

AU - Whitsel, E. A.

AU - Psaty, B. M.

AU - Avery, C. L.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P < 5 x 10(-8)), we found suggestive evidence (P < 5 x 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

AB - Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P < 5 x 10(-8)), we found suggestive evidence (P < 5 x 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

KW - BLOOD-PRESSURE RESPONSE

KW - INFLUENCING ANTIHYPERTENSIVE RESPONSE

KW - GENE-ENVIRONMENT INTERACTIONS

KW - WIDE ASSOCIATION

KW - GENOMEWIDE ASSOCIATION

KW - HYPERTENSIVE PATIENTS

KW - CARDIOVASCULAR DRUGS

KW - SELECTION BIAS

KW - UNITED-STATES

KW - VARIANTS

U2 - 10.1038/tpj.2017.10

DO - 10.1038/tpj.2017.10

M3 - Article

C2 - 28719597

SN - 1470-269X

VL - 18

SP - 215

EP - 226

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 2

ER -

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

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Keywords

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