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Influence of Genetic Variation in PDE3A on Endothelial Function and Stroke
Hypertension ( IF 8.3 ) Pub Date : 2020-02-01 , DOI: 10.1161/hypertensionaha.119.13513
Matthew Traylor 1, 2 , Ali Amin Al Olama 1 , Leo-Pekka Lyytikäinen 3, 4 , Sandro Marini 5, 6, 7 , Jaeyoon Chung 5, 7 , Rainer Malik 8 , Martin Dichgans 8, 9 , Mika Kähönen 10, 11 , Terho Lehtimäki 3, 4 , Christopher D Anderson 5, 6, 7, 12 , Olli T Raitakari 13, 14 , Hugh S Markus 1
Affiliation  

We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9–12 years of age; β[SE], 0.38 [0.070]; P=3.8×10−8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02–1.06]; P=5.2×10−6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24–27 years; β[SE], 0.47 [0.23]; P=0.047) but not in older adults (β[SE], −0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.

中文翻译:

PDE3A 基因变异对内皮功能和中风的影响

我们的目的是描述内皮功能的遗传学特征,以及它如何影响缺血性中风等心血管疾病的风险。我们将来自ALSPAC(雅芳家长和儿童纵向研究;n=5214)青少年超声血流介导的肱动脉扩张研究的遗传数据与缺血性中风研究(MEGASTROKE:n=60 341 例和 452 969 例)进行了整合。对照)来识别通过改变内皮功能而带来缺血性中风风险的变异。我们发现了编码磷酸二酯酶 3A 的 PDE3A(磷酸二酯酶 3A)中的一个变体,该变体与青少年(9-12 岁;β[SE],0.38 [0.070];P=3.8×10−8 )并带来缺血性中风的风险(比值比,1.04 [95% CI,1.02–1.06];P=5.2×10−6)。贝叶斯共定位分析表明,相同的潜在变异可能导致两种关联(后验概率,97%)。在另一项针对年轻人(年龄,24-27 岁;β[SE],0.47 [0.23];P=0.047)的研究中,相同的变异与血流介导的扩张相关,但在老年人中则不然(β[SE], −0.012[0.13];P=0.89)。我们得出的结论是,PDE3A 的遗传变异会影响生命早期的内皮功能,并导致缺血性中风的风险增加。受遗传影响的脉管系统微妙的、可测量的变化也会影响缺血性中风的风险。
更新日期:2020-02-01
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