Genetic exploration of targeting the transient receptor potential cation channel subfamily member 6.

IF 2.2 4区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Christian Graesser, Nikita Panyam, Xiaofeng Qian, Tan An Dang, Benedikt Niedermeier, Michael Winkler, Johannes Riechel, M Amin Sharifi, Christin Noecker, Carla Abrahamian, Alexander Dietrich, Hendrik B Sager, Heribert Schunkert, Ling Li, Thorsten Kessler
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Abstract

The transient receptor potential cation channel subfamily member 6 (TRPC6) represents an emerging druggable target with a broad therapeutic spectrum. TRPC6 Inhibitors are currently investigated for focal segmental glomerulosclerosis (FSGS), acute respiratory distress syndrome due to COVID-19, and pulmonary hypertension. In the cardiovascular system, there is evidence that TRPC6 is critically involved in the development of cardiac hypertrophy, arrhythmia susceptibility and risk of restenosis after coronary stent implantation. However, data on systemic effects of TRPC6 modulation remain scarce. To assess the phenotypic consequences of inhibiting TRPC6 in different organ systems, we explored public databases to identify single nucleotide polymorphisms (SNPs) that are associated with TRPC6 expression in different tissues. A phenome-wide association study was then performed in 475,739 individuals of UK Biobank to associate genetically-mediated reduced TRPC6 expression with 64 phenotypes in nine organ/disease categories. Lower TRPC6 expression was nominally associated with reduced risk of anxiety, heart failure, and stroke, as well as an increased risk of venous thromboembolism, hypertension, appendicitis and liver cirrhosis. After correction for multiple testing, lower TRPC6 expression remained significantly associated with reduced risk of coronary artery disease and atrial fibrillation. Notably, no deleterious phenotypes were observed, suggesting a favorable profile of systemic TRPC6 inhibition. While these findings indicate potential therapeutic benefits, nominally associated phenotypes, however, mandate careful clinical investigation and provide a basis for further experimental exploration.

靶向瞬时受体电位阳离子通道亚家族成员的遗传探索
瞬时受体电位阳离子通道亚家族成员6 (TRPC6)是一个具有广泛治疗谱的新兴药物靶点。TRPC6抑制剂目前正在研究用于局灶节段性肾小球硬化(FSGS)、COVID-19引起的急性呼吸窘迫综合征和肺动脉高压。在心血管系统中,有证据表明TRPC6在冠状动脉支架植入术后心肌肥厚、心律失常易感性和再狭窄风险的发生中起关键作用。然而,关于TRPC6调节的全身效应的数据仍然很少。为了评估抑制TRPC6在不同器官系统中的表型后果,我们探索了公共数据库,以确定与不同组织中TRPC6表达相关的单核苷酸多态性(snp)。随后,在UK Biobank的475,739名个体中进行了一项全现象关联研究,以将遗传介导的TRPC6表达降低与9个器官/疾病类别中的64种表型联系起来。名义上,较低的TRPC6表达与焦虑、心力衰竭和中风风险降低以及静脉血栓栓塞、高血压、阑尾炎和肝硬化风险增加有关。经过多次检测校正后,较低的TRPC6表达仍然与降低冠状动脉疾病和房颤的风险显著相关。值得注意的是,没有观察到有害的表型,这表明TRPC6的系统性抑制是有利的。虽然这些发现表明潜在的治疗益处,但名义上相关的表型需要仔细的临床研究,并为进一步的实验探索提供基础。
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来源期刊
CiteScore
5.10
自引率
3.30%
发文量
367
审稿时长
1 months
期刊介绍: Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.
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