Genetic Variation in Drug Targets

Drugs act by binding molecular targets - receptors, enzymes, ion channels, and transporters - and inherited variation in the genes encoding those targets can change how strongly a drug works at a given concentration. Unlike variation in metabolizing enzymes, which mostly affects how much drug reaches the target, target-gene variation affects the pharmacodynamic response itself. This topic addresses how variation in the drug's site of action contributes to differences in efficacy.

Definition

Genetic variation in drug targets is inherited DNA variation in the genes encoding a drug's molecular target or the signalling components immediately downstream of it, which alters the magnitude or nature of the drug's biological effect at a given drug concentration (a pharmacodynamic effect).

Scope

The topic covers genetic variation in the proteins drugs act upon and in the pathways immediately downstream of them, the distinction between pharmacodynamic and pharmacokinetic variation, and illustrative target genes whose variants alter drug sensitivity. It is reference material on the mechanism of target-related variability and does not provide drug-specific dosing recommendations.

Core questions

• How does inherited variation in a drug's target change the response to that drug?
• How does target (pharmacodynamic) variation differ from metabolizing-enzyme (pharmacokinetic) variation?
• Which kinds of targets - receptors, enzymes, channels - are subject to functionally important variation?
• Why can two people with identical drug exposure still respond differently?

Key concepts

• Pharmacodynamic versus pharmacokinetic variation
• Receptor, enzyme, ion-channel, and transporter targets
• Target sensitivity and drug efficacy
• Downstream signalling-pathway variants
• Somatic versus germline target variation
• Concentration-effect relationship

Mechanisms

Variants in a target gene can change the amount of target protein expressed, its affinity for the drug, or the efficiency with which target engagement produces a downstream effect. A classic illustration is variation in the vitamin K epoxide reductase gene, which alters sensitivity to warfarin by changing expression of the drug's target enzyme; here the response differs even when drug concentration is the same, marking it as a pharmacodynamic effect. Variation can be germline (inherited and present in all cells) or, in oncology, somatic (acquired in tumour tissue), and it can lie in the target itself or in the signalling network through which the target acts.

Clinical relevance

Target-gene variation helps explain why some patients respond poorly or unusually to a drug despite achieving expected drug levels, and it is part of the rationale for studying pharmacodynamic biomarkers alongside metabolic ones. As reference content this topic describes the mechanism of target-related variability; it does not constitute prescribing guidance, which belongs to validated clinical guidelines applied by qualified clinicians.

Epidemiology

Functionally relevant target-gene variants, such as those affecting warfarin sensitivity, occur at frequencies that differ between ancestral populations, contributing to population-level differences in drug response that parallel those seen for metabolizing-enzyme variants.

History

As genotyping matured after the Human Genome Project, attention broadened from metabolizing enzymes to the targets of drug action. The demonstration by Rieder and colleagues in 2005 that variants in the warfarin target gene VKORC1 explained a substantial part of dose variability was a landmark in establishing pharmacodynamic, target-based genetic variation as a distinct and clinically meaningful contributor to drug response.

Key figures

• Mark Rieder
• Allan Rettie
• Liewei Wang
• Richard Weinshilboum

Seminal works

• rieder-2005
• wang-2011

Frequently asked questions

How is drug-target variation different from drug-metabolism variation?

Drug-metabolism variation changes how much active drug is present (a pharmacokinetic effect), whereas drug-target variation changes how the body responds to a given amount of drug (a pharmacodynamic effect); both can alter the overall response.

Is genetic variation in drug targets always inherited?

Not always. In cancer pharmacology the relevant target variation is often somatic, meaning it arises in tumour cells rather than being inherited, whereas the germline target variants discussed here are present from birth in all of a person's cells.