Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies

Abstract

β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers.

Keywords: Antihypertensive response; Beta-blocker; Biomarker; Hypertension; microRNA.

Fig. 1.

A flow chart representing study design. miRNAs that were significantly differentially expressed between responders and non-responders in the discovery phase were included in the validation phase. BP: Blood Pressure; PEAR-2: Pharmacogenomic Evaluation of Antihypertensive Responses-2 clinical trial; PEAR: Pharmacogenomic Evaluation of Antihypertensive Responses clinical trial; qRT-PCR: Quantitative Reverse Transcription Polymerase Chain reaction.

Fig. 2.

Relative expression of the microRNAs that showed the same direction of differential expression in both in the discovery phase and the validation phase. Bar chart represents the fold change of the differentially expressed miRNA (miR-19a, miR-101, and let-7e) between responders (R) and non-responders (NR) to the antihypertensive effect of the β-blocker metoprolol in the discovery phase and atenolol in the validation phase. Numbers represent P-value of Mann-Whitney U test.