Pharmacogenomics

Genotype to phenotype

Pharmacogenomics uses a patient’s genotype to choose a drug or dose. Most genes involved encode drug-metabolizing enzymes (cytochrome P450s and others), drug targets, or HLA molecules that trigger immune reactions.

Variant combinations are named with star alleles: 1 is usually the reference (normal function), and others are numbered as discovered. Each allele is assigned a function (normal, decreased, no function, increased), and the diplotype is translated to a phenotype* ¹:

• Poor metabolizer (PM): two no-function alleles.
• Intermediate metabolizer (IM): one normal and one no-function allele, or similar combinations.
• Normal metabolizer (NM).
• Rapid / ultrarapid metabolizer: increased-function alleles (or gene duplications, for CYP2D6).

Whether a phenotype raises or lowers drug exposure depends on the drug:

• Active drug cleared by the enzyme: poor metabolizers accumulate drug and risk toxicity.
• Prodrug activated by the enzyme (clopidogrel by CYP2C19, codeine by CYP2D6): poor metabolizers make less active drug and get less effect; ultrarapid metabolizers of codeine make dangerous amounts of morphine.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes guidelines that translate genotypes into prescribing actions.

Clopidogrel and CYP2C19

Clopidogrel is an antiplatelet prodrug that needs CYP2C19 for activation. CYP2C19 *2 and *3 are no-function alleles, and *17 is increased function ¹. Intermediate and poor metabolizers taking clopidogrel have less platelet inhibition and more major cardiovascular and cerebrovascular events ¹.

CPIC 2022, for acute coronary syndrome or PCI ¹:

• Poor metabolizers (*2/*2, *2/*3): avoid clopidogrel if possible; use prasugrel or ticagrelor (strong).
• Intermediate metabolizers (*1/*2, *1/*3): avoid standard-dose clopidogrel if possible; use prasugrel or ticagrelor (upgraded to strong in 2022).

For stroke or TIA, an alternative P2Y12 inhibitor is considered for IMs and PMs; prasugrel is contraindicated after stroke ¹.

Warfarin: CYP2C9 and VKORC1

Warfarin needs careful dosing: too little allows clots, too much causes bleeding. Two genes have the largest effects:

• CYP2C9 metabolizes the more potent S-warfarin; *2 and *3 reduce function, so carriers clear warfarin more slowly and need lower doses.
• VKORC1 encodes warfarin’s target, vitamin K epoxide reductase. The -1639G>A promoter variant reduces VKORC1 expression, so carriers are more sensitive and need lower doses.

CYP2C9, VKORC1, CYP4F2, and a CYP2C cluster variant (rs12777823), together with clinical factors (age, weight, interacting drugs), explain about half of warfarin dose variability ². CPIC recommends genotype-informed dosing algorithms with ancestry-specific guidance, since important variants differ between populations ².

HLA and severe drug reactions

Some HLA alleles present drug-altered peptides to T cells, triggering life-threatening immune reactions ³:

Carbamazepine and HLA-B*15:02: strongly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) with carbamazepine and oxcarbazepine. CPIC: if a patient is carbamazepine-naive and B15:02-positive, don’t use carbamazepine (strong) ⁴. B15:02 is common in parts of East and Southeast Asia (frequencies are high in Thai and Vietnamese populations and lower in Japanese and Korean ones) ⁴. HLA-A*31:01 is linked to SJS/TEN, DRESS, and maculopapular rash with carbamazepine, and carriers should avoid it when alternatives exist ⁴.

Abacavir and HLA-B*57:01: carriers risk a serious, sometimes fatal hypersensitivity reaction. FDA labeling recommends screening before starting abacavir, and positive patients shouldn’t receive it; routine screening cut hypersensitivity from about 8% to under 0.5% ⁵.

Allopurinol and HLA-B*58:01: severe cutaneous reactions ³.

Others to know

• TPMT and NUDT15 with thiopurines (azathioprine, mercaptopurine): poor metabolizers develop severe myelosuppression on standard doses.
• DPYD with fluoropyrimidines (5-fluorouracil, capecitabine): deficient patients risk severe toxicity.
• CYP2D6 with codeine and tramadol (prodrugs) and many antidepressants.
• HER2 / trastuzumab and other tumor biomarkers are pharmacogenomics in the broad sense (covered in the oncology course).

What to take from this

Star alleles combine into poor, intermediate, normal, and rapid metabolizer phenotypes; poor metabolizers accumulate active drugs but under-activate prodrugs. CYP2C19 *2/*3 poor and intermediate metabolizers should avoid clopidogrel for ACS/PCI and take prasugrel or ticagrelor. CYP2C9 *2/*3 and VKORC1 -1639A lower warfarin dose needs. HLA-B*15:02 means no carbamazepine in drug-naive patients, HLA-B*57:01 means no abacavir, and HLA-B*58:01 flags allopurinol risk.