A loss-of-function mutation in a gene is a genetic variant that prevents proper gene expression, preventing it from performing its function in a normal manner. Previous research has shown that loss-of-function mutations in the genes PCSK9, APOC3, ANGPTL3, LPA, and ASGR1 can have beneficial effects on the distribution of blood biomarkers in individuals, such as a reduction in the plasma levels of risk factors for cardiovascular disease such as of low-density cholesterol or triglycerides. A regulatory variant is a genetic mutation that affects the level at which a gene is expressed but isn’t as binary as a loss-of-function variant. Regulatory variants can have a varied effect on the amount, timing, or location of gene activity. They affect how genes are transcribed and translated, leading to specific proteins that will be used for different processes such as lipid metabolism, inflammation, and cardiovascular health.
This study aims to confirm the relationships between regulatory variants in the above-mentioned genes and their impact on cardiovascular biomarker levels and the risk of coronary artery disease. These genes play vital roles in lipid metabolism and cardiovascular health, but the regulatory regions controlling their expression have not been fully explored, particularly within large-scale datasets like the UK Biobank. Understanding the role of regulatory variants can potentially lead to a novel target validation method by demonstrating a genetics-based dosage response curve to target inhibition. This would allow for researchers to definitively prove that variation in the expression levels of a specific gene is associated with changes in specific blood biomarker levels. This would allow for the identification of new inhibitory drug targets to reduce cardiovascular risk factors such as cholesterol and triglycerides with a higher level of certainty much earlier in the drug development process.