Lecture 10 - Pharmacogenetics & Pharmacogenomics pt2

• CYPs

  • Highly polymorphic in the human population
  • Multiple genetic variations or alleles
• CYP2D6

  • Clinically important polymorphic enzyme
  • Metabolizing approximately 20% of drugs modified by CYPs
  • Over 100 different variants (alleles) in the human population
• Polymorphisms of CYP2D6

  Can alter enzyme activity, leading to different metabolic rates for drugs and affecting drug responses in individuals
• CYP2D6 polymorphisms

  • Poor metabolizers may not activate prodrugs like codeine, leading to no pain relief
  • Ultra-metabolizers may experience excessive morphine production from codeine, causing toxicity
• Polymorphisms in other CYPs, such as CYP2A, CYP2B, CYP2C, CYP2E, and others, can also impact drug metabolism and response, with variations in caffeine metabolism being another example
• Treatment with anti-EGFR monoclonal antibodies (mAb)


  Can stop the growth of EGFR(+) tumors
• EGFR(-) tumors

  Are unaffected by anti-EGFR mAb treatment, indicating EGFR-independent proliferation
• Tumors with activating mutations in RAS signaling

  Lead to receptor-independent proliferation, meaning anti-EGFR mAb treatment would be unsuitable and a waste of money
• ALOX5 gene


  Encodes the enzyme arachidonate 5-lipoxygenase, which synthesises leukotrienes, lipid signaling molecules that recruit and activate immune cells, leading to inflammation
• ALOX5 inhibitors


  Are used to treat asthma by stopping the production of leukotrienes
• ALOX5 gene

  • Has Variable Number of Tandem Repeats (VNTR) in the promoter region, which affects transcription factor binding and gene expression
  • Different VNTR sites (3, 4, or 6x) result in low levels of ALOX5 expression, meaning no response to 5-lipoxygenase inhibitors as the asthma is caused by a different pathway
• Drug metabolism

  The conversion of drugs into metabolites, which can be either active or inactive, and is primarily carried out by enzymes in the body
• Signalling pathways


  Complex networks of proteins that communicate and coordinate various cellular processes, including those involved in drug response and pharmacodynamics (PD)
• GWAS (Genome Wide Association Studies)


  An unbiased "agnostic screen" that aims to identify genetic causes of variation in drug response at the genomic level
• GWAS relies on very large patient cohorts to have sufficient statistical power
• GWAS


  Can reveal novel genes that alter drug PK (pharmacokinetics) or PD (pharmacodynamics) by identifying genetic variants associated with altered drug response
• GWAS studies have successfully identified genetic variants in genes encoding cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and can be highly polymorphic
• Genetic variation in CYPs

  Can influence drug PK by altering the metabolism of drugs, leading to differences in drug levels in the body
• GWAS studies


  Have also identified genetic variants in genes involved in signaling pathways, such as epidermal growth factor receptors (EGFR) in cancer cells, which can influence drug PD by altering the response of tumor cells to anti-EGFR monoclonal antibodies, leading to differences in tumor growth inhibition
• GWAS has been used extensively to identify genetic causes of variation in non-infectious diseases, but it is less used for pharmacogenomics due to the need for very large patient cohorts
• The current knowledge is heavily biased towards genetic causes of variation in drug response in Europeans, highlighting the need for more diverse representation in GWAS studies in pharmacogenomics