4: Pharmacogenomics and Variation in Drug Response

4.0 Overview of Pharmacogenomics

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications that can be prescribed based on a person’s genetic makeup. This development suggests that “personalized medicine” may be a possibility.

Many currently available drugs are presented as “one size fits all,” but significant genetic variations in drug metabolism exist between individuals. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects or an unintended drug event. Unintended drug reactions are a significant cause of hospitalizations and deaths in the United States, as discussed in Chapter 6.

Variants (polymorphisms) in genes impact an individual’s response to drugs, such as the variants in Phase I and Phase II drug metabolizing enzymes and drug transporters. Data regarding these genetic differences is used to predict whether a drug will be effective for an individual and which dose will help prevent unintended drug reactions. Knowledge about an individual’s genetic makeup and subsequent response to certain drugs include clopidogrel resistance, warfarin sensitivity, warfarin resistance, malignant hyperthermia, Stevens-Johnson syndrome/toxic epidermal necrolysis, and thiopurine S-methyltransferase deficiency.

Pharmacogenomics is being used to develop tailored drugs to treat a wide range of health problems, including cancer, depression, cardiovascular disease, Alzheimer’s disease, and asthma.

The field of pharmacogenomics is growing, and researchers have identified common types of genetic variation called single nucleotide polymorphisms (SNPs), which are responsible for variations in drug response.

4.1 Single nucleotide polymorphisms

Single nucleotide polymorphisms, or SNPs, are the most common type of genetic variation among humans. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA (Figure 4.1).

The highlighted area shows a strand of DNA with a SNP. Instead of C paired with G as expected, C is paired with T representing a single nucleotide substitution.

DNA Strand with a SNP

SNPs occur normally throughout a person’s DNA. On average, SNPs occur almost once in every 1,000 nucleotides, meaning roughly 4 to 5 million SNPs in a person's genome. To be classified as a SNP, a variant must be found in at least 1% of the population. Scientists have found more than 600 million SNPs in populations around the world.

Most SNPs do not affect health or development. Some of these genetic differences, however, have proven very important in the study of human health. Some SNPs are associated with a gain of function in an enzyme or transport protein, whereas other SNPs are associated with a loss of function in an enzyme or transport protein. SNPs help predict susceptibility to environmental factors such as toxins, the risk of developing diseases, and an individual’s response to certain drugs. SNPs in drug-metabolizing enzymes, drug transporters, and drug targets significantly contribute to the individual variation in response to a drug.

An audio definition of SNPs is available from the National Human Genome Research Institute’s Talking Glossary of Genetic Terms, available from the National Institutes of Health.

4.2 Phase I Enzymes, Genetic Variation and Drug Metabolism

Phase I reactions convert a drug to a more polar form; polarized drugs are more easily excreted. Phase I enzymes include the very important and carefully studied cytochrome P450 (CYP450) superfamily. These enzymes are found in a high concentration in the endoplasmic reticulum of the liver and in other cells throughout the body. CYP450 enzymes are not very selective for their substrate (molecules or drugs the enzyme acts on), so a relatively small number of isoforms of the enzymes metabolize most drugs. CYP2D6, CYP2C19, and CYP3A4/5 metabolize over 75% of the drugs acted on by this superfamily and are among the isoenzymes best studied.

The CYP2D6 gene is highly polymorphic, with over 100 polymorphisms identified; nine variants are common. CYP2D6 polymorphisms are important clinically as commonly used drugs, such as sedatives (midazolam, diazepam, diphenhydramine), anti-depressants (fluoxetine, amitriptyline), anti-arrhythmics (amiodarone), beta-blockers (carvedilol, metoprolol), and pain medications (codeine, tramadol). Polymorphisms are important in individuals who are prescribed codeine because it is a prodrug. Recall that prodrugs are inert chemicals that must be converted to their active form in the body. In the case of codeine, the 2D6 enzyme converts the drug to its active metabolite, morphine. Figure 4.2.1 depicts the differences between a parent drug (starting compound) and a prodrug.

Parent Drugs vs Prodrugs

​​​​​​

CYP2C19 metabolizes a few clinically important drugs, including clopidogrel, propranolol, omeprazole, and diazepam. Again, clopidogrel is a prodrug, and individuals who cannot metabolize it to its active metabolite will not experience anti-platelet benefits.

CYP3A4 and CYP3A5 are responsible for many of the drugs currently in use. Polymorphisms of these enzymes exist but do not contribute as significantly to clinical efficacy and management of drugs for chronic conditions metabolized by CYP2D6 and CYP2C19.

Multiple enzyme polymorphisms may contribute to a drug’s efficacy and tolerability. One well-studied example is warfarin. Warfarin is manufactured as S and R-isomers. The isomers differ in their chemical properties. CYP2C9 and vitamin K reductase epoxide complex subunit 1 (VKORC1) inactivate the S-isomer. Polymorphisms and mutations in the genes which code for these enzymes may cause individuals to have spontaneous bleeding or increased warfarin levels.

4.3 Phase II Enzymes, Genetic Variation and Drug Metabolism

Phase II enzymes reactions, which include reactions to make a drug more water soluble—such as glucuronation, acetylation, and methylation—also have polymorphism in other enzyme families. Making a drug more water soluble allows it to be excreted.

Multiple enzyme polymorphisms may contribute to a drug’s efficacy and tolerability. One well-studied example is warfarin. Warfarin is manufactured as S and R-isomers. The isomers differ in their chemical properties. CYP2C9 and vitamin K reductase epoxide complex subunit 1 (VKORC1) inactivate the S-isomer. Polymorphisms and mutations in the genes that code for these enzymes may cause individuals to have increased response to warfarin and spontaneous bleeding. Patients may be screened for genetic variants in these genes.

Enzymes that regulate Phase II reactions also have polymorphisms. Uridine 5”-diphospho (UDP) glucuronosyltransferase (UGT1A1) and thiopurine S-methyltransferase (TPMT) are important in the treatment of cancer. These enzymes metabolize chemotherapeutic drugs; polymorphisms may result in altered therapeutic efficacy and toxicities.

4.4 Transport Proteins and Polymorphisms

The SLCO1B1 gene codes for the organic anion transporter (OATP), which transports drugs and other compounds from blood into hepatocytes. Substrates for OATP include statins and methotrexate. Numerous SNPs have been found in the SLCO1B1 gene and are associated with elevated statin levels, especially simvastatin and increased risk of skeletal myopathy.

The ABCB1 gene codes for P-glycoproteins (P-gp), an efflux protein found on blood-tissue interfaces such as the blood–brain barrier, intestines, and placenta. The P-gps performs a very important function, expelling foreign compounds from the cell. Sometimes described as promiscuous, the P-gps can bind to many drugs and compounds. It is associated with expelling cytotoxic drugs from resistant cancer cells.

4.5 Human Leukocyte Antigen (HLA) and Polymorphisms

Human leukocyte antigen (HLA) are genes that code for proteins that are responsible for identifying self from non-self. They play a significant role in immune defense/transplant rejection and are highly variable. HLA polymorphisms are associated with immunological responses to drugs such as liver injury, Stevens-Johnson syndrome, and toxic epidermal necrosis. Carbamazepine has been associated with HLA polymorphisms.

Phase I and Phase II enzymes, transport proteins and HLA all have polymorphisms, which contribute to the variation in response to drug efficacy and tolerability. Personalized medicine takes into account the person’s genetic factors or genotype that may potentially contribute to the response to a drug and drug efficacy. Much is known about the identification of specific genes that affect drug pharmacokinetics. Although this knowledge is not complete and continues to unfold, our understanding of the relationship between genotype and phenotype has allowed the development of guidelines to direct prescribing based on the person’s genotype. To fully comprehend this process, we need to discuss metabolizing phenotypes.

4.6 Drug Metabolizing Phenotypes

We inherit one gene from each parent. The variation in the DNA sequence of a gene is called an allele. Individuals may be homozygous (two identical alleles) or heterozygous (two different alleles). Alleles coding for the CYP450 superfamily enzymes and the other metabolizing enzymes are named with standardized * nomenclature. The *1 designation (wild type) is the referent to which all alleles are compared and codes for what is considered the “normally” functioning enzyme. The enzyme activity of each allele is assessed and categorized in reference to the functional *1 allele. Some alleles have less activity (loss of function), whereas other alleles confer increased activity (gain of function). The functional phenotype or metabolizer status results from the combined effect of both alleles and is categorized using standardized nomenclature. Poor, intermediate, normal (wild type), rapid, and ultrarapid phenotypes describe the spectrum of possible enzyme activity.

Recall figure 4.2, which illustrated the metabolism of a parent drug compared to a prodrug. Prodrugs require conversion to an active form by metabolizing enzymes. Knowing whether a prescribed medication is a prodrug or not helps clinicians anticipate the clinical effects of altered enzyme metabolism and the risk of unintended drug events, drug-drug interactions, and therapeutic failures. Figure 4.5.1 illustrates the relationship between parent drugs, prodrugs and metabolizer status. The categories and definitions of the metabolizing phenotypes are: (1) normal metabolizers with two fully functional alleles; (2) rapid metabolizers with gain of function alleles and high enzyme activity; (3) ultrarapid metabolizers have higher enzyme activity than rapid metabolizers; (4) intermediate metabolizers with decreased enzyme activity compared to normal metabolizers; and (5) poor metabolizers with loss of function alleles with little to no enzyme activity. The relationship between drug concentration and enzyme phenotype is opposite in parent drug vs a prodrug that must be converted into an active metabolite. Normal metabolizers are most likely to experience therapeutic benefits, but persons with other metabolizing phenotypes may experience a range of benefits and toxicities.

Parent Drugs, Prodrugs and Metabolizer Status

Ideally, identifying a person’s metabolizing phenotype may help avoid therapeutic failures and unintended events. Many healthcare systems are implementing pharmacogenomic testing and strategies. Genetic testing may be embedded in the person’s electronic health record (EHR), which is then available to all clinicians. Consortiums have been developed that curate and centralize pharmacogenetic information to support and facilitate pharmacogenetic testing. PharmVar, the Pharmacogene Variation Consortium, and PharmGKB are resources supported by the National Institutes of Health for this purpose. The Clinical Pharmacogenetic Implementation Consortium (CPIC) produces evidence-based guidelines on actionable gene-drugs, including statements for adults and pediatrics. The Food and Drug Administration (FDA) lists detailed additional data support management recommendations and how drug labels have incorporated pharmacogenetic data.

Clinical implementation of pharmacogenetic data is a challenge. Many questions remain unanswered regarding best practices for selecting genetic testing, interpreting test results, and maintaining confidentiality.

Related websites:

CPIC
ClinGen Pharmacogenomic Working Group
Royal Dutch Pharmacists Association-Pharmacogenetics Working Group

This chapter titled Pharmacogenomics and Variation in Drug Response is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Karen Vuckovic from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz (MIT OpenCourseWare) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures by Riley Cutler.