Genetic Exploration of Targeting the Transient Receptor Potential Cation Channel Subfamily Member 6

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.