Cholesterol biosynthesis is a very complex and highly regulated metabolic process, in which the final product is well-characterized, but the metabolic intermediates are less so.
Focusing on the last ten distal reactions of cholesterol biosynthesis, which we can classify in Bloch and Kandutsch-Russell pathways, it has been seen that these enzymes and their metabolites (CBIs) play a fundamental role in human physiology and that their perturbations lead to pathological effects, such as Mendelian syndromes caused by inborn error of cholesterol biosynthesis.
Research suggests that several genetic variations in these enzymes are linked to an increased risk of neurodegenerative diseases, while their overexpression has also been observed in certain types of cancer.
This suggests that the sterol intermediates of cholesterol biosynthesis do not only act as precursors of cholesterol but that they are also involved in other physiological roles, beyond cholesterol production.
In this study we will associate rare, coding and non-coding genetic variants in genes of CBIs with clinical and molecular phenotypes, to understand in which pathologies they are implicated in, and we will perform combinatorial genetics analysis to determine the putative signaling mediators of these intermediates.
Despite the extensive knowledge about cholesterol, limited information is available on the molecular functions its distal intermediates. Considering how crucial cholesterol synthesis is, and that several widespread drugs target it, it is imperative to deeply understand the roles of CBIs outside of their function as biochemical precursors of cholesterol. The aim of this project is to improve the knowledge about CBIs and CBI genes through analysis on a large database such as UKBioBank.
