Pharmacogenomics: when your genes change how you respond to a drug
Star alleles, metabolizer status, and the ten FDA Black Box drug-gene alerts Haeckel surfaces. Concrete examples from CYP2D6 codeine and DPYD fluorouracil.
Pharmacogenomics studies how variation in your genome changes the way your body absorbs, activates, breaks down, or responds to a drug. About one in five drugs sold in the United States carries a label warning that one or more genetic variants alter its safety or efficacy, and for ten of those the FDA has issued a Black Box warning that requires the prescriber to confirm the genotype before writing the prescription.
Star alleles, briefly
Most pharmacogenes have many catalogued variants, and the field uses a notation called star alleles to bundle each variant under a short identifier. CYP2D6*1 is the reference. CYP2D6*4 is a loss-of-function allele common in European populations. CYP2D6*10 is a reduced-function allele common in East Asian populations. A diplotype like CYP2D6*1/*4 names both copies you carry.
Each star allele carries an activity score that ranges from zero (loss of function) through 0.5 (reduced function) to 1 (normal) and beyond. Sum the activity scores across both copies and the result classifies you as a poor, intermediate, normal, rapid, or ultra-rapid metabolizer for that gene.
Concrete examples
Codeine itself is a prodrug. Your liver converts codeine into morphine using CYP2D6. A poor metabolizer experiences little to no analgesia. An ultra-rapid metabolizer can produce dangerously high morphine levels from a standard dose, which has led to fatal overdoses in children.
DPYD encodes the enzyme that breaks down 5-fluorouracil and capecitabine, two backbone chemotherapy drugs. About 1 in 30 people carries a DPYD variant that reduces enzyme function, and giving such a patient a standard chemotherapy dose can cause life-threatening toxicity. CPIC guidelines recommend a 50% dose reduction or switching agents.
About 5 to 8% of people of European ancestry carry HLA-B*57:01, a variant that is strongly associated with a severe and sometimes fatal hypersensitivity reaction to the HIV drug abacavir. The FDA mandates HLA-B*57:01 testing before prescription.
The ten Black Box alerts Haeckel surfaces
- CYP2D6 with codeine, tramadol, and several antidepressants.
- CYP2C19 with clopidogrel.
- CYP2C9 with warfarin and phenytoin.
- DPYD with fluorouracil and capecitabine.
- HLA-B*57:01 with abacavir.
- HLA-B*15:02 with carbamazepine in patients of East Asian ancestry.
- TPMT with thiopurines.
- NUDT15 with thiopurines.
- UGT1A1 with irinotecan.
- SLCO1B1 with simvastatin and other statins.
- CPIC: Clinical Pharmacogenetics Implementation Consortium guidelines, cpicpgx.org.
- PharmGKB: pharmgkb.org.
- FDA Table of Pharmacogenomic Biomarkers in Drug Labeling, fda.gov.
Are there any drugs I should be careful about based on my pharmacogenomic profile?