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Genetic Exploration of Targeting the Transient Receptor Potential Cation Channel Subfamily Member 6
Christian Graesser1,2, Nikita Panyam1,2, Xiaofeng Qian1
1Department of Cardiology, German Heart Centre, TUM University Hospital, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
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, 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.
Insights
Inhibiting the TRPC6 channel may offer systemic benefits, potentially reducing risks for coronary artery disease and atrial fibrillation without observed negative effects. Further research is warranted for clinical application.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Genetics
Background:
- Transient receptor potential cation channel subfamily member 6 (TRPC6) is an emerging drug target for various diseases.
- TRPC6 inhibitors are under investigation for focal segmental glomerulosclerosis, COVID-19 ARDS, and pulmonary hypertension.
- TRPC6 plays a role in cardiovascular conditions like cardiac hypertrophy, arrhythmias, and restenosis, but systemic effects of its modulation are not well understood.
Purpose of the Study:
- To investigate the systemic phenotypic consequences of TRPC6 inhibition across different organ systems.
- To associate genetically-mediated reduced TRPC6 expression with various phenotypes using a phenome-wide association study.
Main Methods:
- Exploration of public databases to identify single nucleotide polymorphisms (SNPs) linked to TRPC6 expression.
- Phenome-wide association study (PheWAS) in 475,739 UK Biobank participants.
- Association analysis of genetically reduced TRPC6 expression with 64 phenotypes across nine organ/disease categories.
Main Results:
- Lower TRPC6 expression was nominally linked to reduced risks of anxiety, heart failure, and stroke.
- Increased risks were nominally associated with venous thromboembolism, hypertension, appendicitis, and liver cirrhosis.
- After multiple testing correction, significantly reduced risks for coronary artery disease and atrial fibrillation were observed, with no deleterious phenotypes identified.
Conclusions:
- Genetically-mediated lower TRPC6 expression suggests a potentially favorable systemic profile for TRPC6 inhibition.
- Findings support potential therapeutic benefits of TRPC6 inhibition, particularly for cardiovascular diseases.
- Nominally associated phenotypes require careful clinical investigation and further experimental validation.
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