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. Méndez-Giráldez, 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. Stürmer, F. R. Rosendaal, K. D. Taylor, K. L. Wiggins, J. G. Wilson, Y. Di Chen, Robert 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. V. Smith, B. H. Stricker, C. C. Laurie, J. I. Rotter, E. A. Whitsel, B. M. Psaty, C. L. Avery

Research output: Contribution to journalArticle

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, trans-ethnic 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 × 10-8m), we found suggestive evidence (P<5 × 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 languageEnglish (US)
Pages (from-to)215-226
Number of pages12
JournalPharmacogenomics Journal
Volume18
Issue number2
DOIs
StatePublished - Apr 1 2018

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Thiazides
Sodium Chloride Symporter Inhibitors
Single Nucleotide Polymorphism
Epidemiology
Genome
Research
Population
Ion Transport
Hispanic Americans
African Americans
Antihypertensive Agents
Cardiac Arrhythmias
Phenotype
Pharmacogenomic Testing

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations : The cohorts for heart and aging research in genomic epidemiology. / 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.; Busch, E. L.; Duan, Q.; Stilp, A. M.; O'Donnell, C. J.; Macfarlane, P. W.; Floyd, J. S.; Kors, J. A.; Lin, H. J.; Li-Gao, R.; Sofer, T.; Méndez-Giráldez, R.; Cummings, S. R.; Heckbert, S. R.; Hofman, A.; Ford, I.; Li, Y.; Launer, L. J.; Porthan, K.; Newton-Cheh, C.; Napier, M. D.; Kerr, K. F.; Reiner, A. P.; Rice, K. M.; Roach, J.; Buckley, B. M.; Soliman, E. Z.; De Mutsert, R.; Sotoodehnia, N.; Uitterlinden, A. G.; North, K. E.; Lee, C. R.; Gudnason, V.; Stürmer, T.; Rosendaal, F. R.; Taylor, K. D.; Wiggins, K. L.; Wilson, J. G.; Chen, Y. Di; Kaplan, Robert C.; Wilhelmsen, K.; Cupples, L. A.; Salomaa, V.; Van Duijn, C.; Jukema, J. W.; Liu, Y.; Mook-Kanamori, D. O.; Lange, L. A.; Vasan, R. S.; Smith, A. V.; Stricker, B. H.; Laurie, C. C.; Rotter, J. I.; Whitsel, E. A.; Psaty, B. M.; Avery, C. L.

In: Pharmacogenomics Journal, Vol. 18, No. 2, 01.04.2018, p. 215-226.

Research output: Contribution to journalArticle

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, Méndez-Giráldez, 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, Stürmer, T, Rosendaal, FR, Taylor, KD, Wiggins, KL, Wilson, JG, Chen, YD, Kaplan, RC, Wilhelmsen, K, Cupples, LA, Salomaa, V, Van Duijn, C, Jukema, JW, Liu, Y, Mook-Kanamori, DO, Lange, LA, Vasan, RS, Smith, AV, Stricker, BH, Laurie, CC, Rotter, JI, 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
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. ; Busch, E. L. ; Duan, Q. ; Stilp, A. M. ; O'Donnell, C. J. ; Macfarlane, P. W. ; Floyd, J. S. ; Kors, J. A. ; Lin, H. J. ; Li-Gao, R. ; Sofer, T. ; Méndez-Giráldez, R. ; Cummings, S. R. ; Heckbert, S. R. ; Hofman, A. ; Ford, I. ; Li, Y. ; Launer, L. J. ; Porthan, K. ; Newton-Cheh, C. ; Napier, M. D. ; Kerr, K. F. ; Reiner, A. P. ; Rice, K. M. ; Roach, J. ; Buckley, B. M. ; Soliman, E. Z. ; De Mutsert, R. ; Sotoodehnia, N. ; Uitterlinden, A. G. ; North, K. E. ; Lee, C. R. ; Gudnason, V. ; Stürmer, T. ; Rosendaal, F. R. ; Taylor, K. D. ; Wiggins, K. L. ; Wilson, J. G. ; Chen, Y. Di ; Kaplan, Robert C. ; Wilhelmsen, K. ; Cupples, L. A. ; Salomaa, V. ; Van Duijn, C. ; Jukema, J. W. ; Liu, Y. ; Mook-Kanamori, D. O. ; Lange, L. A. ; Vasan, R. S. ; Smith, A. V. ; Stricker, B. H. ; Laurie, C. C. ; Rotter, J. I. ; Whitsel, E. A. ; Psaty, B. M. ; Avery, C. L. / Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations : The cohorts for heart and aging research in genomic epidemiology. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 2. pp. 215-226.
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T1 - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations

T2 - 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 - Méndez-Giráldez, 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 - Stürmer, T.

AU - Rosendaal, F. R.

AU - Taylor, K. D.

AU - Wiggins, K. L.

AU - Wilson, J. G.

AU - Chen, Y. Di

AU - Kaplan, Robert 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. V.

AU - Stricker, B. H.

AU - Laurie, C. C.

AU - Rotter, J. I.

AU - Whitsel, E. A.

AU - Psaty, B. M.

AU - Avery, C. L.

PY - 2018/4/1

Y1 - 2018/4/1

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, trans-ethnic 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 × 10-8m), we found suggestive evidence (P<5 × 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, trans-ethnic 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 × 10-8m), we found suggestive evidence (P<5 × 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.

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