Approximately 3% of the global population receives long term glucocorticoid (GC) therapy. However, prolonged GC exposure often leads to glucocorticoid induced osteoporosis (GIOP). It is characterised by a rapid loss of bone mass, deterioration of bone microarchitecture, and a markedly increased risk of fragility fractures, contributing substantially to the GC user morbidity and mortality. To better understand the multifaceted nature of GIOP, this research seeks to use clinical, genetic, pharmacological, and molecular data collected by UK Biobank to make a holistic analysis and overview. Specifically, it aims to characterise how population characteristics, glucocorticoid type and metabolism, dosage and treatment duration interact with genetic and proteomic factors to influence individual sensitivity, susceptibility and percentage of people developing GIOP under GC use.
Research questions tackled in this project:
* How does population related factors, e.g., sex, age, ethnicity, and body mass index influence susceptibility or severity of GIOP?
* How does interindividual sensitivity to different synthetic glucocorticoids, influence the risk of developing GIOP?
* Is there interaction between individual glucocorticoid sensitivity, treatment duration and cumulative glucocorticoid exposure with respect to the risk and severity of GIOP?
* Are there single nucleotide polymorphisms that associate with GIOP development and severity, and fracture risk?
* Do genetic variants in the glucocorticoid receptor (NR3C1) and various glucocorticoid response elements modulate glucocorticoid sensitivity and susceptibility to GIOP?
* Is the systemic proteomic profile altered in individuals receiving glucocorticoid therapy, and are these changes associated with GIOP?
* Does CYP3A5 and CYP3A4 activity caused by the polymorphisms for these enzymes influence GC side effect (such as GIOP) occurrence?