What is pharmacogenomics

Pharmacogenomics is how DNA variation and drugs interact and how this can optimise patient health; this involves studying pharmacokinetics and pharmacodynamics. Pharmacokinetics is the variability of how the drug interacts with the body, e.g., absorption, distribution, metabolism, and elimination. Pharmacodynamics is the variability of the drug interactions with its effector molecules and variability in disease mechanisms. There are many different reasons for individual variability in drug response, although we will focus on examples of how the genome affects drug response. A patient with one of these variants may experience severe and life-threatening adverse events when exposed to certain drugs. These events are the leading cause of morbidity and death in the United States; more than 90% of patients are thought to carry at least one genetic variant.

How can genetic variations produce significant drug response effects?

Two scenarios demonstrate how single gene variants which affect pharmacokinetics have significant effects.

Administrations of prodrugs

The first is the administration of prodrugs, e.g., aspirin, psilocybin, parathion, irinotecan, codeine, and heroin. Prodrugs are pharmacologically inactive substances that require bioactivation by drug metabolism to achieve their therapeutic effects. These bioactivation pathways involve a single drug metabolising enzyme; a genetic variation resulting in loss-of-function of these enzymes can significantly impact drug action, potentially blocking it. An example of this includes the bioactivation of codeine to morphine by CYP2D6 and the bioactivation of clopidogrel by CYP2C19. However, there are differences in bioactivation between those heterozygous or homologous expressions.
When the dose of clopidogrel is increased, there is an observed antiplatelet effect in heterozygotes for CYP2C19*2, which is a loss of function variant, indicating that they can still produce functional CYP2C19; homozygous CYP2C19*2 results in a complete lack of functional CYP2C19. Although the effect of CYP2C19*2 is significant, the total variability in clopidogrel due to this variant is 12%. A gain of function variants in bioactivation has been reported, associated with excessive drug response. Examples include CYP2C19*17, which has been associated with bleeding during clopidogrel therapy and CYP2D6 duplications associated with excess narcotic effects, including respiratory arrest.

Warfarin

Warfarin is a well-studied example of a drug whose variable actions are determined by pharmacokinetics and pharmacodynamics variants. Warfarin is administered as a racemate, and bioactivated is through CYP2C9. Loss of function variants for CYP2C9 results in an increase in active warfarin (S-warfarin) plasma concentration resulting in an increased pharmacological effect and increased risk of bleeding. Variants CYP2C9*2 and CYP2C9*3 are common in people of European ancestry; CYP2C9*3 reduces activity more significantly than CYP2C9*2. If patients are heterozygous for CYP2C9*2, then there is only a tiny pharmacogenomic effect; those homologous for CYP2C9*3 experience a dramatic decrease in the required warfarin dose. Loss of function variants for VKORC1, identified through traditional genetic linkage methods, are responsible for the rare syndrome of familial warfarin resistance. Further studies showed that VKORC1 encodes the warfarin target. A rarer VKORC1 variant reduces function activity, which results in increased warfarin requirement.

Active drugs with a narrow therapeutic window

The second situation is how pharmacokinetic variants can influence the administration of active drugs with a narrow therapeutic range that undergoes elimination through a single system. An example of this is the antileukemic drug 6-mercaptoprine activated by thiopurine S-methyltransferase (TPMT) and xanthine oxidase (XO). A loss of function variant for TPMT results in decreased inactivation, higher parent drug concentrations, and increased generation of cytotoxic thioguanine nucleotide (TGN) metabolites. When there is a homozygous expression of loss of function variants in TPMT, patients will exhibit life-threatening bone marrow toxicity due to TGN accumulation.

Non-dose-dependent ADRs

There is another class of ADRs where the reaction is not related to the drugs' known and intended pharmacological effects; these are often considered non-dose-dependent. These ADRs can include severe immunologically ADRSs such as Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). GWAS (Genome-wide association study) studies have shown the importance of genetics in drug response. For example, HLA-B*15:02 confers a risk of carbamazepine-related SJS/TEN in southeast Asia, where is allele variant is common. This allele is rare in people of European descent, although a different allele has been implicated, HLA-A*31:01, to confer the same risks. However, some of these HLA variants are alone not sufficient to induce an immunological response. An example of this is the HLA-B*57:01 variant implicated in flucloxacillin-related hepatoxicity, although only 1/13,000 positive genotype patients will react, indicating other factors at play.

Gain of function variants

Gain of function variants can result in an ultrarapid metabolisers phenotype resulting in overdoses on opioids, e.g., codeine. Codeine is activated to morphine by CYP2D6, with more than 100 known variations. Patients with the ultra-metaboliser's phenotype have a higher concentration of morphine in their blood increases the risk of severe opioid toxicity. There have been serval incidences of children who were CYP2D6 ultrarapid metabolisers have had severe reactions to codeine; 10 children died, and three others experienced severe respiratory depression. Other opioids are CYP2D6 substrates, e.g., hydrocodone, oxycodone, and tramadol. Poor metaboliser phenotype is brought about through different CYP2D6 variants, and these patients may experience inadequate poor relief because of decreased metabolism.
Antidepressants are among the most prescribed classes of drugs in the United States. However, about 30-50% of initial therapy fails due to ineffectiveness. Antidepressants are metabolised by CYP2D6 or/and CYP2C19. Data suggests that genomic variation in serotonin transporters, e.g., SLC6A4, and receptors, e.g., HTR2A and HTR2C, is associated with antidepressant effectiveness.

Challenges to implementing mass pharmacogenomic testing

There are some challenges to using pharmacogenomic testing on mass. Specific pharmacogenomic variants are common in different ethnic groups; this makes conducting studies difficult as a large study population will be required to reflect all ethnic groups. Another is the hesitance around the cost of testing; in a survey of US payer organisations with over 122 million patients, there was concern about the initial costs and the perceived limited benefits, mainly when then are many low-cost generic drugs that are available before prescribing a new medication that requires a genotyping panel before prescribing.