pharmacogenomics

• Pharmacogenomics


  The study of how an individual's genetic makeup affects their response to drugs
• Precision health


  • Takes both genetic and non-genetic factors into account
  • Often framed as the right treatment, for the right patient, at the right time
• Adverse Drug Reactions (ADRs)

  • Negative / undesirable effects of drug treatment
  • Can influence different systems
  • Severely debilitating and potentially fatal
• ADRs are a serious healthcare burden, being the 4th leading cause of death and accounting for 6.5% of hospital admissions in the United Kingdom
• Factors contributing to differential drug response

  • Clinical
  • Demographic
  • Genetic
• Sex differences in drug response

  • 8 of 10 withdrawn drugs effect women more than men
  • Women underrepresented in the research pipeline

  
• Age and variation in drug response

  • Drug metabolism/elimination less efficient in newborns/elderly
  • More side effects in vulnerable groups due to polypharmacy

  
• Genetic variation


  Can cause altered enzyme activity through regulatory, coding, or splicing changes
• Expression quantitative trait loci (eQTL)

  Examine the association between genetic variants and gene expression levels
• Central dogma


  DNA -> RNA -> Protein
• How genetic factors influence drug response

  • Drug response is heritable
  • Key determinant of response to medication
  • Potential to predict & prevent non-optimal treatments
  • Gain mechanistic insight into disease pathophysiology
• CYP2D6


  An important drug metabolizing enzyme with many genetic variants that can alter its function
• 97% of individuals carry clinically relevant pharmacogenomic variants
• Clinical Practice Guidelines


  • Facilitate genotype guided therapy
  • Standardized, peer-reviewed by the Clinical Pharmacogenetics Implementation Consortium (CPIC)
• Mercaptopurine (6-MP)


  • Chemotherapy drug that can cause myelosuppression
  • Genetic variants in TPMT and NUDT15 genes are linked to toxicity
• Genetic variants in TLR4

  Can confer protection against cisplatin-induced hearing loss
• Pharmacogenomics can help guide drug treatment and understand disease pathophysiology
• Genetic tests can be used to predict which drugs will have adverse effects or not work at all, allowing healthcare providers to make more informed decisions about treatment options.