Pharmacogenomics and Adverse Reactions

## Overview

Pharmacogenomics studies how genetic variation affects drug response. Adverse drug reactions (ADRs) cause approximately 100,000 deaths annually in the US and are the fourth leading cause of death. Genetic factors account for 20-95% of variability in drug response, depending on the drug.

## Pharmacokinetic Pharmacogenomics

**CYP2D6** metabolizes approximately 25% of clinically used drugs. Over 100 allelic variants produce four phenotypes: poor metabolizers (PM), intermediate metabolizers (IM), extensive/normal metabolizers (NM), and ultra-rapid metabolizers (UM). Codeine UMs convert excessive codeine to morphine, risking fatal respiratory depression. PMs get no analgesic benefit from codeine. Tamoxifen PMs have reduced conversion to the active metabolite endoxifen.

**CYP2C19** affects clopidogrel activation. PMs have reduced platelet inhibition and increased cardiovascular event risk. The FDA black box warning recommends alternative antiplatelet therapy for PMs. Conversely, PMs may experience higher esomeprazole exposure (beneficial for acid suppression).

**CYP2C9** and **VKORC1** together explain approximately 40% of warfarin dose variability. CYP2C9 poor metabolizers require lower warfarin doses to avoid bleeding. VKORC1 variants affect vitamin K epoxide reductase sensitivity.

**TPMT and NUDT15** deficiency causes severe myelosuppression with thiopurine drugs (azathioprine, 6-mercaptopurine). Pre-treatment genotyping is now standard, with dose reductions of 50-90% for carriers of loss-of-function alleles.

## Pharmacodynamic Pharmacogenomics

**G6PD deficiency** causes hemolytic anemia upon exposure to oxidative drugs (primaquine, dapsone, rasburicase). Affecting 400 million people worldwide, it is the most common enzyme deficiency.

**Malignant hyperthermia** susceptibility (RYR1 mutations) triggers life-threatening hyperthermia with volatile anesthetics and succinylcholine. Family history screening is critical.

## HLA-Associated Reactions

HLA genotyping has transformed prevention of severe hypersensitivity reactions:

| Gene | Drug | Reaction | Population Risk |
|---|---|---|---|
| HLA-B*57:01 | Abacavir | Hypersensitivity | 5-8% Caucasians |
| HLA-B*15:02 | Carbamazepine | SJS/TEN | 8% SE Asians |
| HLA-B*58:01 | Allopurinol | SJS/TEN/DRESS | 6-8% SE Asians |
| HLA-A*31:01 | Carbamazepine | DRESS | 2-5% Europeans |

## Clinical Implementation

The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides evidence-based guidelines for over 40 gene-drug pairs. Pre-emptive pharmacogenomic testing panels are increasingly integrated into electronic health records, with clinical decision support alerts firing when a high-risk drug is prescribed to a patient with a known actionable genotype.

Barriers include cost, turnaround time, lack of prescriber education, and limited diversity in pharmacogenomic research populations.

## Key Takeaways

- CYP2D6, CYP2C19, CYP2C9, and TPMT are the most clinically actionable pharmacogenes
- Codeine in CYP2D6 ultra-rapid metabolizers can cause fatal respiratory depression
- HLA-B*57:01 testing before abacavir is mandatory and cost-effective
- CPIC provides freely available, evidence-based gene-drug interaction guidelines
- Pre-emptive panel-based genotyping is becoming the standard of care