Population Variation in Pharmacogenetic Alleles

Pharmacogenetic alleles - the variant forms of genes that influence how the body absorbs, metabolizes, transports, and responds to drugs - occur at strikingly different frequencies across human populations. A star allele that is common in one population may be rare or absent in another, so the clinical relevance of a given pharmacogenetic variant depends on the population in which it is considered.

Definition

The differential distribution, across human populations, of allelic variants in genes affecting drug pharmacokinetics and pharmacodynamics, typically described using star (*) allele nomenclature and population allele frequencies.

Scope

This topic describes how and why pharmacogene allele frequencies differ across populations, the major catalogues and sequencing projects that document this variation, and the consequences for which variants matter where. It focuses on the descriptive genetics of variation; it is not a guide to testing or prescribing.

Core questions

• Which pharmacogenes show the largest frequency differences across populations?
• How do star alleles and their functional categories distribute worldwide?
• What data sources document pharmacogene allele frequencies?
• Why do allele frequencies differ - what evolutionary processes drive the pattern?
• How does population variation affect which alleles a test panel must include?

Key concepts

• Star (*) allele nomenclature
• Allele frequency
• Cytochrome P450 (e.g., CYP2D6, CYP2C19, CYP2C9) variation
• Functional allele categories (no-function, decreased-function, normal, increased-function)
• Genetic drift, selection, and migration
• Rare and population-specific variants
• Reference databases (1000 Genomes, ExAC/gnomAD, PharmGKB)

Mechanisms

Variation arises because mutations occur in pharmacogenes and then change in frequency over generations through genetic drift, natural selection, and the bottlenecks and expansions of human migration. The same processes that produced global patterns of neutral variation also distributed functional pharmacogenetic alleles unevenly. Meta-analyses of population-scale sequencing show that for cytochrome P450 genes, which metabolize a large share of clinically used drugs, the predicted distribution of metabolizer phenotypes differs substantially between populations, driven partly by common variants and partly by an abundance of rare, population-specific variants that standard genotyping panels may not capture. African populations, which retain the greatest genetic diversity, carry many variants that are uncommon or unobserved elsewhere, so panels built mainly from European data systematically under-ascertain their pharmacogenetic variation.

Clinical relevance

Whether a pharmacogenetic test or guideline applies well to a patient depends on how completely it captures the alleles prevalent in that patient's population. This entry explains the descriptive basis for that dependence and is not a recommendation about which tests to order or how to act on results, which are matters for validated clinical guidelines and qualified clinicians.

Epidemiology

Catalogues such as the 1000 Genomes Project and large exome and genome aggregations document that allele frequencies for many pharmacogenes vary several-fold across continental and regional populations, and that a substantial fraction of functional pharmacogenetic variation consists of rare variants concentrated in understudied populations.

History

Pharmacogenetics began with mid-twentieth-century observations of inherited differences in drug metabolism, and star-allele nomenclature later standardized how variants are named. The arrival of population-scale sequencing - the 1000 Genomes Project and large exome aggregations in the 2010s - made it possible to quantify pharmacogene allele frequencies worldwide, and meta-analyses such as Zhou and colleagues (2017) mapped the global distribution of cytochrome P450 alleles, underscoring both common-variant differences and a large reservoir of rare variants.

Debates

How should rare and novel pharmacogenetic variants be handled?

Much functional variation is rare and population-specific, falling outside fixed genotyping panels; whether to predict their effects computationally, sequence comprehensively, or expand panels is an open methodological question.

Key figures

• Volker M. Lauschke
• Magnus Ingelman-Sundberg
• Sarah Tishkoff
• Charles Rotimi

Seminal works

• zhou-2017
• 1000genomes-2015
• rotimi-2017

Frequently asked questions

What is a star (*) allele?

Star-allele nomenclature is a standardized system for naming the variant forms of a pharmacogene (for example CYP2D6*4), each defined by specific sequence variants and assigned a functional category. The frequencies of these alleles differ across populations.

Why are rare variants a particular problem?

A large share of functional pharmacogenetic variation consists of rare, often population-specific variants. Fixed genotyping panels designed from well-studied populations may miss them, leaving variation in underrepresented populations under-ascertained.