Baudier Claire, Fougerousse Françoise, Asselbergs Folkert W, Guedj Mickael, Komajda Michel, Kotecha Dipak, Thomas Lumbers R, Schmidt Amand F, Tyl Benoît
Translational Medicine Division, Institut de Recherches Internationales Servier, Suresnes, France.
Center for Therapeutic Innovation Cardiovascular & Metabolic Disease, Institut de Recherches Internationales Servier, Suresnes, France.
Front Cardiovasc Med. 2023 Oct 18;10:1148931. doi: 10.3389/fcvm.2023.1148931. eCollection 2023.
The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.
Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases).
Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74-0.93, = 0.001) and 0.95 (95% CI 0.93-0.97, = 8 × 10). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05-1.12, = 3 × 10). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92-1.07, = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease.
This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.
由于缺乏随机对照试验，α和β肾上腺素能受体调节对心力衰竭（HF）发生风险的影响仍不确定。本研究旨在评估α和β肾上腺素能受体调节对HF风险的影响，并为HF的基因靶点验证研究提供原理证明。
在一项有757,601名参与者的全基因组关联研究（GWAS）中，选择与血压相关的编码肾上腺素能受体α1A、α2B、β1和β2的顺式区域内的基因变异作为工具，进行药物靶点孟德尔随机化研究。这些变异对HF风险的影响来自HERMES GWAS（542,362名对照；40,805例HF病例）。
较低的α1A或β1活性与HF风险降低相关：比值比（OR）为0.83（95%置信区间0.74 - 0.93，P = 0.001）和0.95（95%置信区间0.93 - 0.97，P = 8×10⁻⁴）。相反，较低的α2B活性与HF风险增加相关：OR为1.09（95%置信区间1.05 - 1.12，P = 3×10⁻⁵）。未发现较低的β2活性对HF风险有影响的证据：OR为0.99（95%置信区间0.92 - 1.07，P = 0.95）。补充分析表明，这些影响与对左心室尺寸的影响一致，且独立于对冠状动脉疾病的任何潜在影响。
本研究提供了基因证据，表明抑制α1A或β1受体可能会降低HF风险，而较低的α2B活性可能会增加这种风险。基因变异分析可协助HF预防药物的开发。
