Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics

Ana Caroline C. Sá; Amy Webb; Yan Gong; Caitrin W. McDonough; Somnath Datta; Taimour Y. Langaee; Stephen T. Turner; Amber L. Beitelshees; Arlene B. Chapman; Eric Boerwinkle; John G. Gums; Steven E. Scherer; Rhonda M. Cooper-Dehoff; Wolfgang Sadee; Julie A. Johnson

doi:10.1038/s41598-017-16343-z

Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics

Ana Caroline C. Sá, Amy Webb, Yan Gong, Caitrin W. McDonough, Somnath Datta, Taimour Y. Langaee, Stephen T. Turner, Amber L. Beitelshees, Arlene B. Chapman, Eric Boerwinkle, John G. Gums, Steven E. Scherer, Rhonda M. Cooper-Dehoff, Wolfgang Sadee, Julie A. Johnson

Nephrology and Hypertension

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2 Scopus citations

Abstract

Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10^-11) and TSC22D3 (p = 1.9 × 10^-9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.

Original language	English (US)
Article number	16068
Journal	Scientific reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-16343-z
State	Published - Dec 1 2017

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Sá, A. C. C., Webb, A., Gong, Y., McDonough, C. W., Datta, S., Langaee, T. Y., Turner, S. T., Beitelshees, A. L., Chapman, A. B., Boerwinkle, E., Gums, J. G., Scherer, S. E., Cooper-Dehoff, R. M., Sadee, W., & Johnson, J. A. (2017). Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics. Scientific reports, 7(1), Article 16068. https://doi.org/10.1038/s41598-017-16343-z

Sá, ACC, Webb, A, Gong, Y, McDonough, CW, Datta, S, Langaee, TY, Turner, ST, Beitelshees, AL, Chapman, AB, Boerwinkle, E, Gums, JG, Scherer, SE, Cooper-Dehoff, RM, Sadee, W & Johnson, JA 2017, 'Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics', Scientific reports, vol. 7, no. 1, 16068. https://doi.org/10.1038/s41598-017-16343-z

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title = "Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics",

abstract = "Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10-11) and TSC22D3 (p = 1.9 × 10-9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.",

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doi = "10.1038/s41598-017-16343-z",

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T1 - Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics

AU - Sá, Ana Caroline C.

AU - Webb, Amy

AU - Gong, Yan

AU - McDonough, Caitrin W.

AU - Datta, Somnath

AU - Langaee, Taimour Y.

AU - Turner, Stephen T.

AU - Beitelshees, Amber L.

AU - Chapman, Arlene B.

AU - Boerwinkle, Eric

AU - Gums, John G.

AU - Scherer, Steven E.

AU - Cooper-Dehoff, Rhonda M.

AU - Sadee, Wolfgang

AU - Johnson, Julie A.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10-11) and TSC22D3 (p = 1.9 × 10-9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.

AB - Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10-11) and TSC22D3 (p = 1.9 × 10-9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.

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JO - Scientific reports

JF - Scientific reports

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M1 - 16068

ER -

Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics

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