L1 Pharmacogenetics Overview

Pharmacogenetics: A Historical Overview

• Pharmacogenetics studies hereditary variations in drug responses.
• German geneticist Friedrich Vogel first used the term in 1959, observing variable responses to drugs like isoniazid, primaquine, and succinylcholine in patients with hepatic porphyria.
• Clinical data on variable responses to drugs existed before this, including those related to isoniazid, primaquine, and succinylcholine.
• Drug metabolism is largely handled by CYPs, which are categorized into different groups based on their activity and genetic variability.
  • Ultrarapid metabolizers possess multiple active CYP genes.
  • Extensive metabolizers have two functional CYP genes.
  • Poor metabolizers lack functional CYP enzymes due to defective genes.
  • Intermediate metabolizers have one functional and one defective CYP gene, or two partially defective genes.
• CYPs are responsible for 80% of phase 1 metabolism.

Pharmacogenomics: Expanding Personalized Medicine

• Pharmacogenomics uses human genome information to personalize drug therapy.
• Pharmacogenomics utilizes gene sequencing to select or develop drugs tailored to individual genetic makeups.
• This field includes existing drugs and new drug development.
• The term was coined in 1997.
• Pharmacogenetics is a sub-speciality of pharmacogenomics.

Historical Highlights in Pharmacogenetics

• Pythagoras (6th century BC): Observed adverse reactions to fava beans, now linked to variations in glucose-6-phosphate dehydrogenase (G6PD).
• 1932: Inability to taste phenylthiocarbamide (PTC) identified as genetically inherited, related to the TAS2R38 gene. This gene encodes a taste receptor protein.
• 1950s: Genetic polymorphisms in G6PD, cholinesterase, and acetylation identified. These are associated with adverse reactions to specific drugs
  • Isoniazid (TB treatment): Slow acetylation is associated with peripheral neuritis.
  • Primaquine (malaria treatment): Deficiency in G6PD causes acute haemolysis in some individuals.
  • Succinylcholine (muscle relaxant): Deficiency in cholinesterase results in prolonged paralysis.
• 1970s: Cytochrome P450 polymorphisms described.
• 1980s onwards: Gene cloning allowed for identification of additional polymorphisms and correlations with phenotypes.
• 1990s-2000s: Human Genome Project provided further genome sequence data.
• Present: Genome-wide association studies investigate disease susceptibility and drug response.

Genetic Polymorphisms

• Genetic polymorphisms are mutations with a population frequency of at least 1 in 100.
• Polymorphisms can be base substitutions (SNPs), insertions, or deletions and occur roughly every 1,000 bases.

Functional Polymorphisms

• Functional polymorphisms affect biological activities due to
  • Amino acid substitutions.
  • Transcription factor binding site alterations.
  • Splicing site mutations (e.g. exon skipping).
  • Gene duplications or deletions.

Synonymous and Non-synonymous Mutations

• Synonymous mutations don't alter amino acid sequences.
• Non-synonymous mutations change amino acid sequences and potentially protein function. Examples include base insertions, deletions, missense, nonsense, and non-stop mutations.

Control of CYP Gene Expression

• DNA methylation may regulate CYP gene expression. This mechanisms occurs primarily at CpG sites by DNA methyltransferase enzymes, and can affect transcription factor binding or transcriptional silencing.
• MicroRNAs and changes in mRNA target binding sites or mRNA precursors can influence CYP expression.

Pharmacogenetic Polymorphisms: Consequences

• Consequences of variations in drug responses include drug toxicity and lack of response.
  • Toxicity: Exaggerated response or effect involves an inappropriate target, dependent on the drug's therapeutic window.
  • Lack of response: insufficient drug activity or too-rapid drug metabolism/excretion or failure of prodrug activation; the target dose may not respond or drug may be metabolized/excreted too rapidly.

Identification Approaches

• Phenotypic approaches:
  • Measure enzyme activity or drug metabolite patterns.
  • Problems include tissue accessibility, difficulty in studying drug receptors.
• Genotypic approaches:
  • Examine genes for polymorphisms.
  • More common, due to extensive genome sequencing data (e.g., NOMAD). Data isn't always available for all populations.
  • Advantages include direct gene examination, use of readily available DNA samples (blood, buccal cells, saliva). -Disadvantages include relating polymorphisms to function, which can be technologically complex.