Pharmacogenomic testing: Relevance in medical practice
ABSTRACTGenetics may account for much of the variability in our patients’ responses to drug therapies. This article offers the clinician an up-to-date overview of pharmacogenomic testing, discussing implications and limitations of emerging validated tests relevant to the use of warfarin (Coumadin), clopidogrel (Plavix), statins, tamoxifen (Nolvadex), codeine, and psychotropic drugs. It also discusses the future role of pharmacogenomic testing in medicine.
KEY POINTS
- Polymorphisms that affect the pharmacokinetics and pharmacodynamics of specific drugs are common.
- Testing for certain polymorphisms before prescribing certain drugs could help avoid adverse drug effects and improve efficacy.
- Pharmacogenomic testing has only recently begun to enter clinical practice, and routine testing is currently limited to a few clinical scenarios. However, additional applications may be just around the corner.
- Many pharmacogenomic tests are available, but testing has not yet been recommended for most drugs. Needed are large-scale trials to show that routine testing improves patient outcomes.
In many patients, certain drugs do not work as well as expected, whereas in other patients they cause toxic effects, even at lower doses. For some patients, the reason may be genetic.
Sizeable minorities of the population carry genetic variants—polymorphisms— that affect their response to various drugs. Thanks to genetic research, our understanding of the variability of drug response has advanced markedly in the last decade. Many relevant polymorphisms have been identified, and tests for some of them are available.
Armed with the knowledge of their patients’ genetic status, physicians could predict their response to certain drugs, leading to better efficacy, fewer adverse drug reactions, and a better cost-benefit ratio.
The possible impact is substantial, since more than half of the drugs most commonly involved in adverse drug reactions are metabolized by polymorphic enzymes.1 Adverse drug reactions remain a significant detriment to public health, having a substantial impact on rates of morbidity and death and on healthcare costs.2–8 In the United States, adverse drug reactions are a leading cause of death in hospitalized patients4 and are annually responsible for hundreds of thousands of deaths and hundreds of billions of dollars in added costs.2,4,6–8
In the meantime, physicians can educate their patients and promote efforts to incorporate genomic information into standard clinical decision-making.
This article offers an overview of pharmacogenomic testing, discussing implications and limitations of a few validated tests. Specifically, we will discuss testing that is relevant when using warfarin (Coumadin), clopidogrel (Plavix), statins, tamoxifen (Nolvadex), codeine, and psychotropic medications, as well as the future role of pharmacogenomic testing in medicine.
WHAT IS PHARMACOGENOMICS?
Pharmacogenomics is the study of how genetic factors relate to interindividual variability of drug response.
Many clinicians may not be familiar with the background and terminology used in the pharmacogenomic literature. Below, a brief review of the terminology is followed by a schematic describing the various stages of research involved in pharmacogenomics and the advancement of a test into standard practice.
The review and schematic may be helpful for evaluating the clinical significance of pharmacogenomics-related articles.
From genotype to phenotype
Genotype refers to the coding sequence of DNA base pairs for a particular gene, and phenotype (eg, disease or drug response) refers to a trait resulting from the protein product encoded by the gene. The name of a gene often refers to its protein product and is italicized (eg, the CYP3A4 gene encodes for the CYP3A4 enzyme).
Two alleles per autosomal gene (one paternal and one maternal) form the genotype. Heterozygotes possess two different alleles, and homozygotes possess two of the same alleles. The most common allele in a population is referred to as the wild type, and allele frequencies can vary greatly in different populations.9
Most sequence variations are single nucleotide polymorphisms (SNPs, pronounced “snips”), a single DNA base pair substitution that may result in a different gene product. SNPs can be classified as structural RNA polymorphisms (srSNPs), regulatory polymorphisms (rSNPs), or polymorphisms in coding regions (cSNPs)10: srSNPs alter mRNA processing and translation, rSNPs alter transcription, and cSNPs alter protein sequence and function.
Recently, genetic associations with a phenotype have been done on a large scale, with millions of SNPs measured in each of many subjects. This approach, called a genomewide association study or GWAS, has revealed countless candidate genes for clinical traits, but only a few have resulted in a practical clinical application. SNPs may by themselves exert a pharmacokinetic effect (ie, how the body processes the drug), a pharmacodynamic effect (ie, how the drug affects the body), or both, or they may act in concert with other genetic factors. Pharmacodynamic effects can result from a pharmacokinetic effect or can result from variations in a pharmacologic target.
Establishing a genotype-phenotype association can involve clinical studies, animal transgenic studies, or molecular and cellular functional assays.
Clinical applications are emerging
