Pharmacogenomics
"Pharmacogenomics" (PGx) is a rapidly advancing field that combines pharmacology (the study of drugs) with genomics (the study of genes and their functions). It investigates how an individual's genetic makeup influences their response to drugs.
Key Principles of Pharmacogenomics
The core idea is that variations in our genes can affect how drugs are absorbed, distributed, metabolized, and eliminated (pharmacokinetics), as well as how they interact with their molecular targets in the body (pharmacodynamics). This genetic information can help predict whether a drug will be effective, cause adverse side effects, or require a different dose for a particular patient.
Genetic Variation
- Individuals have unique genetic variations (e.g., single nucleotide polymorphisms – SNPs) that can alter the function of proteins involved in drug processing or action.
Drug Metabolism Enzymes:
Many genes encode enzymes (especially cytochrome P450 enzymes like CYP2D6, CYP2C19, CYP2C9) that metabolize drugs. Variations in these genes can lead to:
- Poor Metabolizers: Break down drugs slowly, leading to higher drug levels and increased risk of side effects.
- Ultra-Rapid Metabolizers: Break down drugs quickly, leading to lower drug levels and potential treatment failure.
- Normal Metabolizers: Break down drugs at an expected rate.
Drug Targets
- Genes can also affect the proteins that drugs bind to (receptors, enzymes, transporters). Variations in these targets can influence how effective a drug is.
Drug Transporters
- Genes encode proteins that transport drugs into and out of cells. Variations can affect drug absorption or distribution.
Immune Response
- Some genetic variations are linked to severe adverse drug reactions due to immune overreactions (e.g., HLA-B*5701 and abacavir hypersensitivity).
Clinical Applications of Pharmacogenomics
PGx testing is already being integrated into clinical practice for several classes of drugs:
Oncology (Pharmacogenomics in Cancer Treatment
- Targeted Therapies: Identifying specific genetic mutations in tumors that make them susceptible to certain drugs (e.g., EGFR mutations in lung cancer, HER2 amplification in breast cancer, BRAF mutations in melanoma).
- Chemotherapy Dosing:
- TPMT (Thiopurine S-Methyltransferase): Genetic variations in TPMT affect the metabolism of thiopurine drugs (e.g., azathioprine, mercaptopurine) used in leukemia, inflammatory bowel disease, and autoimmune conditions. Patients with low TPMT activity are at high risk of severe bone marrow suppression if given standard doses.
- DPYD (Dihydropyrimidine Dehydrogenase): Variations affect the metabolism of 5-fluorouracil (5-FU) chemotherapy; deficiency can lead to severe toxicity.
Cardiology
- Clopidogrel (Plavix): An antiplatelet drug. CYP2C19 genetic variations affect its activation. Poor metabolizers may not convert clopidogrel to its active form effectively, increasing their risk of cardiovascular events.
- Warfarin: An anticoagulant. CYP2C9 and VKORC1 genetic variations influence warfarin dose requirements, affecting bleeding risk or clot prevention.
Pain Management
- Codeine: A prodrug that needs to be converted to morphine by CYP2D6. Ultra-rapid metabolizers can experience severe side effects (e.g., respiratory depression), while poor metabolizers get no pain relief.
HIV Treatment
- Abacavir: An antiretroviral drug. Patients with the HLA-B5701* allele are at high risk of a severe, potentially fatal hypersensitivity reaction. Testing for this allele is mandatory before prescribing abacavir.
Psychiatry
- Antidepressants (SSRIs, TCAs): CYP2D6 and CYP2C19 variations affect the metabolism of many antidepressants, influencing efficacy and side effects.
- Antipsychotics: Similar to antidepressants, metabolism can be affected by CYP enzyme variations.
The Role of the Diagnostic Laboratory:
As our understanding of the human genome and its interaction with drugs continues to grow, pharmacogenomics is poised to become an increasingly integral part of routine medical care, leading to safer and more effective treatments for patients.
Performing Genetic Testing
Using techniques like PCR, DNA sequencing, or microarray analysis to detect specific genetic variations.
Interpreting Results
Providing clear reports that explain the patient's genotype and its predicted impact on drug response (e.g., "CYP2D6 Poor Metabolizer").
Quality Assurance
Ensuring the accuracy and reliability of PGx tests.
Integration
Working with clinicians and pharmacists to integrate PGx results into clinical decision-making.