How to use the Handbook

The UKCPA Handbook of Pharmacogenomics aims to support the use of pharmacogenetic results to optimise medicines by providing healthcare professionals with evidence-based advice and guidance in a simple and easy to use format. 

The UKCPA Handbook of Pharmacogenomics is not intended to offer definitive therapeutic recommendations on how drugs should be used based on pharmacogenetic results. It is not a comprehensive or exhaustive list of drugs which may be affected by pharmacogenetic variation.

The information provided within the UKCPA Handbook of Pharmacogenomics has been compiled from a range of sources and from the clinical experience of pharmacists and healthcare professionals with expertise in pharmacogenomics. Some of the information contained in the handbook may not be in accordance with the UK marketing authorisation (product licence) of the drug. 

For more in-depth information, users are advised to refer to the Summary of Product Characteristics (SmPC) www.emc.medicines.org.uk, the Clinical Pharmacogenetics Implementation Consortium (CPIC®) www.cpicpgx.org, and the Pharmacogenomics Knowledgebase (PharmGKB®) www.clinpgx.org. As content on these websites is subject to updates and modifications, users should refer to the original source to ensure they are accessing the most current content. 

Pharmacogenomics is the study of how an individual's entire genetic makeup influences their response to medication. Genetic variations can influence both how the body processes a drug (pharmacokinetics) and how the drug interacts with the body's systems (pharmacodynamics). 

The terms “pharmacogenomics” and “pharmacogenetics” are often used interchangeably; however, their scope is different. Pharmacogenetics focuses on individual gene-drug interactions, while pharmacogenomics considers the impact of the entire genome, including the interplay of multiple genes and molecular pathways that influence drug response. 

Pharmacogenetic nomenclature, most notably for CYP gene variants, often follows the star allele system. This consists of the name of the gene (e.g., CYP2C19), the star (*) symbol, and a number that represents a specific variant of that gene (*1, *3, *26).

Since an individual has two copies of each gene (one inherited from each parent) an individual’s genotype is reported as a diplotype, with each star allele separated by a (/) (e.g., CYP2C19 *2/*3).

Sometimes “x” is added to indicate the presence of additional copies of the gene known as ‘copy number variants’ (CNVs) (e.g., CYP2D6 *2x2, which signifies two copies of the CYP2D6 *2 variant allele). 

The *1 allele is reported when no variant is detected and infers normal function (see also Testing Technology and Limitations).

Not all types of variants or genes follow the star allele nomenclature. For some genes, individual functional variants are reported directly (e.g., DPYD 1601G>A or MTRNR1 1555A>G). Variants in HLA genes are usually reported as haplotypes (e.g., HLA-B*57-01), referring to a specific combination of variants found together that are predictive of effect.

Allele definitions are maintained by the Pharmacogene Variation Consortium www.PharmVar.org. 

Genotype to phenotype translation is the method by which a genotype (e.g., CYP2C19 *2/*2) is translated into how an individual will metabolise a particular drug (e.g., ‘poor metaboliser’) - the phenotype. Genotype to phenotype translation methods for some genes use an activity score system where each variant or star allele is assigned an activity value. The sum of activity values assigned to each variant gives rise to an activity score which is then translated into the phenotype. Copy number variation, which is found more commonly in some genes (e.g., CYP2D6) can also contribute to activity. 

Whilst effort has been made by international consortia to standardise genotype to phenotype translation methods, users of the Handbook should be aware that reference laboratories, published clinical practice guidelines, and Summary of Product Characteristics (SmPCs) may use varying methods to assign phenotypes. Where genotype to phenotype translation is provided within the UKCPA Handbook of Pharmacogenomics this is in accordance with methods published by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) unless stated otherwise.

For pharmacogenetic tests, laboratories rarely sequence entire genes or interrogate every possible variant position. Instead, they typically use targeted testing methods to identify common variants with known functional effect. Variants which are not tested for will therefore not be reported and, in the absence of any other functional variants, the result will usually be reported as *1 or normal function. Therefore, understanding which variants have been tested for is key in the interpretation of results.

The prevalence of different genotypes may vary between ethnic groups. Some less common variants occur at a higher rate in certain ethnic groups. This means that tests that only identify the most common variants may disproportionately fail to identify people with clinically relevant variants in these groups.

Additionally, some genes are known to be influenced by structural variants such as gene deletions, duplications, copy-number variants and hybrid genes. Not all tests are able to detect and/or quantify structural variants.

Users should be aware of the possibility and impact of limitations with testing methodologies when interpreting pharmacogenetic test results.

Phenoconversion is a mismatch between an individual’s genotype-based prediction of drug metaboliser phenotype, and their true capacity to metabolise drugs due to non-genetic factors. Drug-drug interactions with CYP-inhibiting or CYP-inducing drugs are the major cause of phenoconversion. The effect of drug-drug interactions can be additive to the effect of genotype on drug metabolism and response. Co-morbidities such as cancer and inflammation, smoking, increasing age and pregnancy have also been reported as contributing factors to phenoconversion and can also affect drug metabolism and response.

Although some information on interactions and pharmacokinetic pathways may be included in the monographs, the UKCPA Handbook of Pharmacogenomics is not intended to be used as a drug-interactions or pharmacokinetics resource. Users are advised to consider the impact of drug interactions and other potential causes of phenoconversion when interpreting the therapeutic recommendations and advice in the Handbook. Users should consult the SmPC and/or appropriate drug interactions resources for more detailed advice on drug interactions and pharmacokinetic pathways. 

Most pharmacogenomic studies to date have focused on individuals of European and East-Asian descent. Other groups, such as those of African and Hispanic ancestry, are often under-represented. Users should be aware that pharmacogenomic guidelines primarily reflect data from European and East Asian populations, which may compromise their accuracy for predicting drug responses in other groups. 

The majority of pharmacogenomic research has been conducted in adult populations. Although an individual’s genome, and the variants within, remains largely stable throughout life, the application of pharmacogenomic evidence to paediatric patients requires careful consideration. Developmental changes in gene expression and enzyme function can modify the clinical relevance of pharmacogenomic variants. For example, the impact of poor metaboliser status for enzymes with low intrinsic activity at birth (such as CYP2D6 and CYP2C19) may be minimal in infancy but becomes increasingly pronounced with age.

The UKCPA Handbook of Pharmacogenomics can provide useful guidance on the application of pharmacogenomic testing in children, however, users should exercise caution and consult specialist literature where appropriate.

Where doses are given in the UKCPA Handbook of Pharmacogenomics, these are adult doses unless stated otherwise.