Genetic Polymorphisms and Drug Response

Genetic polymorphisms are common inherited variations in DNA sequence that occur at appreciable frequency in a population. When such variation falls in genes that influence how a drug is processed or how it acts, it can produce measurable, sometimes large, differences in drug response — from loss of efficacy to increased risk of toxicity. This topic covers how polymorphism translates into variable drug response and why it is central to pharmacogenomics.

Definition

A genetic polymorphism is a DNA-sequence variant that occurs in more than a defined minor fraction of a population; in pharmacology it becomes relevant when it alters the function or expression of genes that govern a drug's disposition or its molecular targets, thereby changing drug response.

Scope

The entry covers the nature of genetic polymorphism (including single-nucleotide polymorphisms, insertions and deletions, and copy-number variation), the distinction between variants that affect drug pharmacokinetics and those that affect pharmacodynamics, and the way a genotype is interpreted as a predicted response phenotype. It is a methodological and conceptual reference, not clinical guidance.

Core questions

• What kinds of genetic variation alter drug response?
• How does a variant in a metabolizing enzyme, transporter, or drug target change observed effect?
• Why do the same variants have different consequences for different drugs?
• How is a genotype translated into a predicted response phenotype?

Key concepts

• Single-nucleotide polymorphism (SNP)
• Copy-number variation
• Allele and haplotype
• Star (*) allele nomenclature
• Genotype-to-phenotype prediction
• Pharmacokinetic versus pharmacodynamic variants
• Minor allele frequency and population variation

Mechanisms

A polymorphism can change drug response through several routes. Variants in genes encoding metabolizing enzymes or transporters change the rate of drug clearance or uptake, altering systemic and tissue concentrations (a pharmacokinetic effect). Variants in genes encoding drug targets or downstream effectors change the response produced by a given concentration (a pharmacodynamic effect). Some variants alter immune recognition and predispose to hypersensitivity reactions. Functional alleles are commonly catalogued using a star-allele nomenclature and combined into diplotypes that are translated into predicted phenotypes — for example, reduced or enhanced metabolic capacity — which in turn inform expectations about efficacy and toxicity (Evans & McLeod, 2003; Wang, McLeod & Weinshilboum, 2011).

Clinical relevance

Recognizing that common polymorphisms can shift drug response helps explain unexpected non-response or adverse reactions and motivates genotype-aware appraisal in clinical pharmacology. This is reference material describing how variation relates to response; it does not prescribe testing or dosing for individual patients.

Epidemiology

Functionally relevant pharmacogenetic polymorphisms are widespread, and most people carry several. Allele frequencies differ markedly between ancestral populations, so the clinical importance of a given variant — and the proportion of people predicted to have an atypical response — depends on the population considered (Wang, McLeod & Weinshilboum, 2011).

Evidence & guidelines

Curated resources and consortia, including the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC), assemble and grade the evidence linking specific polymorphisms to drug response and define which gene-drug pairs are considered clinically actionable (Evans & McLeod, 2003).

History

The recognition that inherited variation governs drug response predates molecular biology, but the systematic cataloguing of polymorphisms accelerated with DNA sequencing and the Human Genome Project. Evans and Relling's 1999 synthesis reframed individual pharmacogenetic observations as part of a genome-wide, mechanistic account of variable drug response.

Debates

Single-variant versus polygenic prediction of drug response

Much pharmacogenetics rests on individual high-impact variants, but many drug responses are influenced by multiple variants of small effect, and how far polygenic scores add clinical value beyond single actionable variants is unsettled.

Key figures

• William Evans
• Mary Relling
• Howard McLeod
• Richard Weinshilboum

Seminal works

• evans-relling-1999
• evans-mcleod-2003
• wang-2011

Frequently asked questions

What makes a DNA variant a polymorphism rather than a mutation?

Conventionally, a variant is called a polymorphism when it occurs in a population above a defined minor-allele frequency; rarer variants are often called mutations, though the boundary is a matter of convention rather than biology.

Does carrying a pharmacogenetic variant always change my response to a drug?

No. A variant only matters for drugs whose handling or action depends on the affected gene, and its effect can also be modified by dose, other drugs, organ function, and additional genetic factors.