Table of Contents

  1. Definition & Scope
  2. Key Concepts
  3. Mechanisms of Genetic Influence
  4. CRISPR Technology in Pharmacogenetics
  5. Practical Applications
  6. Real-World Problem: Adverse Drug Reactions
  7. Latest Discoveries
  8. Surprising Facts
  9. References

Definition & Scope

Pharmacogenetics is the study of how genetic variation among individuals influences their response to drugs. It focuses on single gene variations and their impact on drug metabolism, efficacy, and toxicity.

  • Pharmacogenomics (broader term): Involves the study of how all genes (the genome) can influence responses to drugs.
  • Goal: Personalize medicine to maximize efficacy and minimize adverse effects.

Key Concepts

1. Genetic Polymorphisms

  • Single Nucleotide Polymorphisms (SNPs): The most common type of genetic variation affecting drug response.
  • Copy Number Variations (CNVs): Duplications or deletions of gene segments impacting drug metabolism.

2. Drug Metabolizing Enzymes

  • Cytochrome P450 Enzymes (CYPs): Responsible for metabolizing ~75% of all drugs.
    • CYP2D6, CYP2C19, CYP2C9 are highly polymorphic and clinically relevant.

3. Drug Targets

  • Genetic variation in drug targets (e.g., receptors, enzymes) can alter drug efficacy.

4. Transporters

  • Variants in transporter genes (e.g., SLCO1B1) affect drug absorption and distribution.

Mechanisms of Genetic Influence

Diagram: Genetic Influence on Drug Response

Genetic Influence on Drug Response

Key Mechanisms:

  • Altered Enzyme Activity: Polymorphisms can lead to poor, intermediate, extensive, or ultra-rapid metabolism.
  • Modified Drug Targets: Changes in receptors or enzymes can reduce or enhance drug efficacy.
  • Transporter Variants: Affect drug entry into cells or organs, influencing therapeutic outcomes.

CRISPR Technology in Pharmacogenetics

CRISPR-Cas9 enables precise gene editing, allowing researchers to:

  • Validate gene-drug interactions: By editing specific genes in cell lines or animal models.
  • Create isogenic cell lines: Useful for studying the functional impact of variants.
  • Potential for clinical correction: Inherited pharmacogenetic defects could be corrected in the future.

Diagram: CRISPR Mechanism

CRISPR Mechanism

Practical Applications

1. Personalized Drug Dosing

  • Warfarin: Dosing guided by CYP2C9 and VKORC1 genotypes.
  • Clopidogrel: CYP2C19 poor metabolizers have reduced response.

2. Avoidance of Adverse Drug Reactions (ADRs)

  • Carbamazepine: HLA-B15:02* allele carriers at risk for Stevens-Johnson syndrome.
  • Abacavir: HLA-B57:01* screening prevents hypersensitivity.

3. Drug Development

  • Target validation: Identifying genetic subgroups for clinical trials.
  • Biomarker discovery: Predictive markers for efficacy and safety.

Real-World Problem: Adverse Drug Reactions

ADRs are a major cause of morbidity and mortality. Genetic variability in drug metabolizing enzymes and immune response genes is a key contributor.

  • Example: Statin-induced myopathy is linked to SLCO1B1 variants.
  • Impact: Preemptive pharmacogenetic testing can reduce hospitalizations and healthcare costs.

Latest Discoveries

Polygenic Risk Scores in Pharmacogenetics

  • Recent research integrates multiple genetic variants into polygenic risk scores (PRS) to predict drug response more accurately than single-gene tests.
  • 2022 Study: Vojinovic et al., Nature Communications demonstrated that PRS can predict statin efficacy and risk of adverse reactions, improving patient stratification.

CRISPR-Based Functional Validation

  • 2021: CRISPR screens identified novel genes influencing chemotherapy sensitivity, enabling the development of genotype-guided cancer therapies.

Population Diversity

  • 2020-2023: Large-scale sequencing projects (e.g., All of Us Research Program) have uncovered rare pharmacogenetic variants in underrepresented populations, highlighting the need for diverse reference panels.

Surprising Facts

  1. Over 90% of people carry at least one actionable pharmacogenetic variant, but fewer than 10% are routinely tested before drug prescription.
  2. CRISPR-edited cell lines have revealed that some β€œbenign” gene variants can unexpectedly alter drug response under certain environmental conditions.
  3. Pharmacogenetic testing is now integrated into electronic health records in some hospitals, enabling real-time clinical decision support.

References

  • Vojinovic, D., et al. (2022). Polygenic risk scores for statin efficacy and adverse effects. Nature Communications, 13, 1562. Link
  • U.S. National Library of Medicine. Pharmacogenomics Fact Sheet
  • All of Us Research Program. Genomic Data

End of Study Guide