UK Biobank validation of 'loss-of-function' gene variants associated with changes in phenotypic expression of cardiovascular biomarkers and disease.
Approved Research ID: 85442
Approval date: April 25th 2022
A loss-of-function mutation in a gene is when a gene carries a genetic variant that prevents it from performing its function in a normal manner. It has been previously shown that the concept of using a drug to inhibit a specific gene (artificially induce a loss-of-function) can work to lower specific disease risk and improve bodily health. The question has now shifted to focus on which genes would serve as good targets for pharmaceutical inhibition.
This study aims to confirm previously reported relationships between loss-of-function variants in nine genes with an impact on both cardiovascular biomarker levels and incidence risk of coronary artery disease. While some of the genes we will be validating for this study do have a large amount of research behind them (and some even already have drugs made to target them specifically), it is important to note that within the UK Biobank specifically these associations have not been made and that evaluating them together helps keep things grounded in a cardiovascular focus and serves as a proof of concept that our approach does indeed work as intended. Validating the impact of loss-of-function variants in these genes on a scale such as the UK Biobank's genetic database will allow us to form a better understanding of the effect these variants can have when induced in genes relevant to a specific physiological pathway. The inference gained from this initial part of the study will then be used to help guide how we can implement the reverse approach, where we will focus on desirable cardiovascular health outcomes initially and see if we can find novel loss-of-function variants amongst these individuals that could be associated directly with these beneficial outcomes. The idea being that these novel variants could serve as suitable drug targets for future research.
The project is expected to take a maximum of fifteen months to reach completion. The envisioned public health impact is that the initial validation of the association between loss-of-function variants in the nine target genes will increase collective knowledge, allowing for further understanding of genes like PCSK9 who have large scale drug development currently underway and the other genes who might serve as suitable targets for similar drug research. The impact of the exploration of the reverse approach lies in finding novel and effective ways to identify more loss-of-function variants that confer beneficial health outcomes, and thus could serve well as drug targets.