根据阿尔茨海默病中 APOE-ϵ4 等位基因和 ACE 插入/缺失多态性确定血管紧张素调节剂的药物遗传学。

IF 3.8 4区 医学 Q1 Medicine Acta Neuropsychiatrica Pub Date : 2023-12-01 Epub Date: 2023-08-22 DOI:10.1017/neu.2023.38
Fabricio Ferreira de Oliveira, Sandro Soares de Almeida, Elizabeth Suchi Chen, Marilia Cardoso Smith, Paulo Henrique Ferreira Bertolucci
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引用次数: 1

摘要

目的:在阿尔茨海默病(AD)患者中,血管紧张素II受体阻滞剂(ARBs)可减轻脑血管功能障碍,而血管紧张素转换酶抑制剂(ACEis)可能会通过抑制血管紧张素转换酶1(一种淀粉样蛋白-β降解酶)的作用而增加脑淀粉样蛋白-β。然而,血管紧张素转换酶抑制剂可通过减少淀粉样前体蛋白的淀粉样蛋白生成过程、中枢胆碱能和抗炎机制以及外周葡萄糖稳态调节,使 AD 患者受益。我们的目的是研究ACE插入/缺失多态性是否与AD患者的临床变化有关,同时考虑载脂蛋白E(APOE)-ϵ4携带者状态和血压对血管紧张素调节剂的反应:通过认知测试和人体测量对连续门诊的晚发性AD患者进行筛查,同时询问其照顾者的功能和照顾者负担评分。考虑到 APOE-ϵ4 携带者身份和 ACE 插入/缺失多态性基因型,以及 ACEis 或 ARBs 治疗情况,对一年的前瞻性药物遗传学关联进行了估算:在 193 名患者(67.4% 为女性,53.4% 为 APOE-ϵ4 携带者)中,ACE 插入/缺失多态性处于哈代-温伯格平衡状态(p = 0.281),80.3% 的患者患有动脉高血压(n = 124 使用 ACEi,n = 21 使用 ARB)。在照顾者负担变化、认知和功能衰退方面,ARBs 主要使 APOE-ϵ4 携带者受益。由于改善了血压控制以及可能的中枢机制,ACE 类药物使 APOE-ϵ4 非携带者在认知和功能衰退方面受益。ACE插入/缺失多态性导致神经系统结果和血压变化对血管紧张素调节剂的不同反应:结论:血管紧张素调节剂可能是AD的疾病调节剂,建议在临床研究中对样本进行基因分层。
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Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease.

Objective: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators.

Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

Results: For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

Conclusion: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

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来源期刊
Acta Neuropsychiatrica
Acta Neuropsychiatrica 医学-精神病学
CiteScore
8.50
自引率
5.30%
发文量
30
审稿时长
6-12 weeks
期刊介绍: Acta Neuropsychiatrica is an international journal focussing on translational neuropsychiatry. It publishes high-quality original research papers and reviews. The Journal''s scope specifically highlights the pathway from discovery to clinical applications, healthcare and global health that can be viewed broadly as the spectrum of work that marks the pathway from discovery to global health.
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