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

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://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/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 ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.原发性高血压仍是全球疾病负担的首要危险因素，但其治疗目标常难以达成。本研究旨在探究DNA甲基化（DNA methylation）与利尿剂（diuretic）、β受体阻滞剂（beta-blocker）、钙通道阻滞剂（calcium channel blocker）或血管紧张素Ⅱ受体拮抗剂（angiotensin receptor antagonist）的降压应答是否存在关联。此外，鉴于本课题组前期发现儿茶酚胺生物合成相关ACY3基因转录起始位点（Transcription Start Site, TSS）处的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）与β受体阻滞剂的血压（Blood Pressure, BP）应答存在关联，本研究专门分析了ACY3 TSS附近的甲基化位点与β受体阻滞剂的血压应答之间的关联。本研究在两个芬兰高血压队列中开展了白细胞DNA甲基化与降压单药治疗血压应答之间的表观全基因组关联研究（Epigenome-Wide Association Study, EWAS）：分别为GENRES研究（https://clinicaltrials.gov/ct2/show/NCT03276598；每日予氨氯地平5mg、比索洛尔5mg、氢氯噻嗪25mg或氯沙坦50mg）与LIFE-Fin研究（https://clinicaltrials.gov/ct2/show/NCT00338260；每日予阿替洛尔50mg或氯沙坦50mg）。每个单药治疗组的受试者数量约为200例。本研究鉴定出64个甲基化位点提示存在关联（P值原文未明确具体阈值）；其中，ACY3 TSS附近的甲基化位点在GENRES研究中与比索洛尔治疗的收缩压应答存在关联，但未达到全基因组显著性水平（P值原文未明确具体阈值）。本研究结果提示，ACY3基因的遗传与表观遗传变异可能在机体对β受体阻滞剂的血压应答中发挥作用。