Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization
Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization
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DOI：
10.1093/eurheartj/ehaa238
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发表时间：
2020-09-14
影响因子：
39.3
通讯作者：
Chowienczyk, Phil
中科院分区：
文献类型：
--
作者：
Cecelja, Marina;Keehn, Louise;Chowienczyk, Phil
血压（BP）的血流动力学决定因素包括心输出量（CO）、全身血管阻力（SVR）和动脉僵硬度。我们研究了这些表型的遗传性、它们与BP相关的单核苷酸多态性（SNP）的关系以及BP与动脉僵硬度之间的因果关系。方法和结果我们评估了BP、中心BP组分和血液动力学特性（在单次访视期间），包括3531例（1934例单卵型，1586例双卵型）女性TwinsUK参与者的CO、SVR和脉搏波速度（PWV，动脉硬度的测量）。使用结构方程模型估计遗传力。用最小绝对收缩选择算子（LASSO）和广义估计方程回归分析与984个BP相关SNP的关联。单样本和双样本孟德尔随机化（MR）被用来估计BP和动脉僵硬度之间的因果关系，包括436 419名英国生物银行参与者的数据。我们发现BP（>50%）和PWV（65%）的收缩和搏动分量具有高遗传性，重叠基因占观察到的相关性的50%以上。环境因素解释了CO和SVR的大部分变异性（>80%）。回归鉴定出已知与BP相关的SNP（n = 5）也与PWV相关。单样本MR显示TwinsUK参与者BP和PWV之间存在双向因果关系的证据。双样本MR证实PWV对血压（IVW β = 0.11，P < 0.02）和血压对动脉硬化度（IVW β = 0.004，P < 0.0001）有双向因果关系。结论血压的遗传基础不仅由血压调节基因介导，也由影响动脉硬化度的基因介导。孟德尔随机化表明BP和动脉僵硬度之间存在双向因果关系。
Aims Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness.Methods and results We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001).Conclusion The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness.