Identification and evaluation of chronopharmacogenomic (Chrono-PGx) variants

Genomics England Research Registry ID: 581

Registered: 30/04/2021

Expert Summary

Existing approved drugs have complex pharmacological pathways that can be influenced by diurnal or seasonal regulation. This can guide future functional validation and define potential of the field of chrono-pharmacogenomics. Genes associated with one periodic property and pharmacogenetics will be called chronopharmacogenes.

Known pathogenic variants of the enriched chronopharmacogenes will be interrogated for known rare disease association.
The associations identified in the initial analysis will pinpoint whether any licensed drugs can have an in silico predicted diurnal or seasonal dosing optimisation based on their pharmacology, and the feasibility of functional validation.

We will then identify the basis for circadian and seasonal expression in these genes by characterising the promoter elements to identify the E box motifs and any novel elements shared by these genes. We will perform constraint analysis on the characterised promoter elements to identify key residues.
Moreover, certain disease mechanisms have been shown to be influenced by circadian mechanisms and these may be exploited to identify novel drug targets or repurpose existing drugs.

Further work will help identify patients who could or should have different chronotherapeutic dosing information based on their chronopharmacogenomic variants.
• Build a dataset containing variants from dbSNP that are located in the putative circadian cis-elements in promoters of pharmacogenes
• Variants affecting clock promoter motifs of circadian regulated pharmacological targets will be identified in the 100k gene dataset using constraint analysis.

Lay Summary

Life has adapted under the influence of 24-hour day/night cycles, with circadian timekeeping and rhythmicity underpinning many behavioural and physiological mechanisms that anticipate, as well as follow, environment signals. This is also true for annual seasonal cycles but studied to a lesser extent. We will identify which genes demonstrate daily or seasonal periodicity which are also involved with key drug mechanisms. This will enable us to identify which drugs have potential for optimising their administration time of the day or year to achieve the best outcome possible for the patient.
Moreover, certain disease mechanisms have been shown to be influenced by circadian mechanisms and these may be exploited to identify novel drug targets or repurpose existing drugs.