Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design

Marja-Liisa Nuotio, Heini Sánez Tähtisalo, Alexandra Lahtinen, Kati Donner, Frej Fyhrquist, Markus Perola, Kimmo K Kontula, Timo P Hiltunen, Marja-Liisa Nuotio, Heini Sánez Tähtisalo, Alexandra Lahtinen, Kati Donner, Frej Fyhrquist, Markus Perola, Kimmo K Kontula, Timo P Hiltunen

Abstract

Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://ichgcp.net/clinical-trials-registry/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://ichgcp.net/clinical-trials-registry/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.

Keywords: Epigenomics; hypertension; pharmacogenetics; precision medicine.

Conflict of interest statement

The authors report no conflict of interest.

Figures

Figure 1.
Figure 1.
Scatter plots for the most significant correlations between normalized methylation degrees (M-values) and covariate-adjusted blood pressure responses in GENRES. Results from the EWAS analysis are shown as effect sizes and P values. A linear regression line is displayed.
Figure 2.
Figure 2.
P-values for the associations of methylation sites across ACY3 with blood pressure response to bisoprolol in the GENRES Study. Black boxes on the transcript schemes represent coding exons, and white boxes non-coding exons. Lines between boxes depict introns. For methylation (CpG) site numbering (on the abscissa) and precise genomic positioning, see Table 3

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