Germline Pharmacogenetics - PGx

Germline pharmacogenetics describes genetic variations associated with drug response or drug disposition that may predispose a patient to be at risk for drug-related toxicity, nonstandard dose requirements, or a lack of therapeutic benefit. The goals of pharmacogenetic testing are to reduce the high number of nonresponders (on average, 30-60% of patients) and to prevent or reduce adverse drug reactions (ADRs).

ARUP offers single gene testing with predicted pharmacogenetic phenotypes as well as a genotype panel that codes for drug-metabolizing enzymes. The panel includes access to GeneDose LIVE, a cloud-based medication risk management tool. 

Quick Answers for Clinicians

When should pharmacogenetic testing be performed?

Pharmacogenetic testing can be considered before prescribing select drugs in order to detect clinically significant variants that can inform optimal drug and dose decisions, reduce the overall number of nonresponders (approximately 30-60% of patients), and prevent or reduce adverse drug reactions (ADRs). Pharmacogenetic testing may also be relevant when investigating an ADR, including therapeutic failure.

Should I order testing for one gene or several genes?

Whether one gene or several genes should be assessed depends on the reason for testing. When qualifying a person for treatment with a specific drug (eg, abacavir), testing a single gene is appropriate (ie, HLA-B*57:01). If considering treatment with multiple drugs or drugs that are metabolized through multiple routes, a gene panel may be more appropriate.

How should results be interpreted?

Depending on the outcome of the test, certain detected variants may warrant a change in drug dosing or a switch to a different medication. Refer to the Specific Drug-Gene Pair Examples and Associated Tests section for more information on interpretation.

Indications for Testing

Pharmacogenetic testing may be indicated to:

  • Identify clinically significant variants that may guide drug and dose selection to promote personalized therapeutics
  • Predict or explain variant pharmacokinetics and/or pharmacodynamics of specific drugs as evidenced by repeated treatment failures and/or ADRs/toxicity

Guiding Drug and Dose Selection

Pharmacogenetics can be used to predict optimal dosing for select drugs and to avoid ADRs in patients. ADRs include both therapeutic failure and potentially life-threatening toxicities. ADRs are classified as type 1 (dose dependent) and type 2 (not dose dependent). Some drugs (eg, phenytoin) are associated with both type 1 and type 2 ADRs.

Type 1 ADRs

Drugs are administered in either active or inactive forms. Type 1 ADRs occur in response to the dose of a drug, and when the active drug accumulates instead of being eliminated as expected. The target dose of a drug can be adjusted to compensate for differences in active drug accumulation and elimination, thereby minimizing or preventing type 1 ADRs.

​For appropriate dose adjustment, it must be determined whether the risk of an ADR is due to too much active drug (toxicity) or not enough active drug (therapeutic failure).

Graphic showing reaction to drug dosing with arrow pointing up to indicate toxicity, and arrow pointing down to indicate therapeutic failure.

Two mechanisms can reduce the amount of available active drug: (1) transport of a drug away from the site of action, or (2) metabolism. Drug metabolism is frequently accomplished through drug-metabolizing enzymes (eg, CYP2C9, DPYD, TPMT, and UGT1A1). The reactions mediated by the drug-metabolizing enzymes can change an active drug to an inactive form. Metabolic reactions can also change an inactive drug to an active drug, or can change an active drug to another active drug.

The associations between the effect of a gene variant on activity of a specific drug, the target therapeutic dose of that drug, and the likelihood of an ADR are used to apply pharmacogenetic testing to personalize drug therapy.

Note: The metabolic phenotype predicted by pharmacogenetics may be altered by drug-drug interactions (eg, a CYP2C9 normal metabolizer could become a poor metabolizer if the patient takes a medication that inhibits CYP2C9).

How Drug Metabolism Can Affect the Risk of a Type 1 ADR
Type of Metabolic Reaction Drug-Gene Pair Examples Pharmacogenetic Phenotype Predicted
Poor Metabolizer Rapid Metabolizer

Drug is activated by metabolism

Codeine and CYP2D6

or

clopidogrel and CYP2C19

Reduced drug activation

Therapeutic failure likely

Accelerated drug activation

Excess active drug accumulates

Dose-related toxicity possible

Drug is inactivated by metabolism

Nortriptyline and CYP2D6

or

phenytoin and CYP2C9

Poor drug inactivation

Dose-related toxicity possible

Accelerated drug elimination

Therapeutic failure possible

Type 2 ADRs

Type 2 ADRs occur when a person who has inherited a specific gene variant is administered a trigger drug. These reactions can occur regardless of dose; therefore, patients at risk for a type 2 reaction are advised to avoid drugs that could trigger the reaction. Examples include abacavir in patients with the HLA-B*5701 allele, as well as carbamazepine or phenytoin in patients with the HLA-B*1502 allele. In both of these examples, patients who carry at least one affected HLA-B allele are at risk for the associated ADR and should avoid the drug(s).

Dose Optimization

Therapeutic or loading dosing can be calculated for some drugs based on a combination of well-studied pharmacogenetic, demographic, and clinical factors, as well as common drug-drug interactions. The goal of dose calculators and algorithms is to prevent type 1 ADRs. For example, dose calculators can assist in reducing both the time required to achieve a therapeutic response to the anticoagulant drug, warfarin, and the risk of life-threatening bleeding or thrombosis.

An example of a well-respected dose calculator is found at www.WarfarinDosing.org,  a free website that estimates dosing for warfarin. Several other algorithms  have also been developed for warfarin prescribing.

Many of the gene-based dosing guidelines  developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) provide recommended adjustments to standard dosing based on the predicted metabolic phenotype. For example, it is recommended that a 25% reduction in standard dosing of phenytoin  be considered for a CYP2C9 intermediate metabolizer, and that a 50% reduction in standard dosing of phenytoin be considered for a CYP2C9 poor metabolizer. Similar recommendations for dose adjustments based on pharmacogenetic findings are also available in FDA-approved drug labeling. 

Additional Dosing Guidelines

Additional dosing guidelines are available for warfarin.  Dosing guidelines for other drugs are available from the CPIC   and the Pharmacogenomics Knowledgebase (PharmGKB). 

Monitoring for Therapeutic Failure

Drug therapy and dosing should be monitored by clinical exam, biomarker testing, and/or by determining concentrations of drugs and drug metabolites in biological specimens. Monitoring tools are drug and patient specific.

Posttherapeutic evaluation of ADRs or failure to respond is based on clinical factors, the clinical scenario (eg, whether a reaction is likely to be related to the drug and/or dose administered), compliance, the drug, and the drug formulation.

Examples of Therapeutic Failures
Drug Pharmacogenetic Variation(s) Effect
Clopidogrel CYP2C19 Inadequate conversion of parent drug to active metabolite (poor metabolizer)
Codeine, tramadol, oxycodone, tamoxifen CYP2D6 Inadequate conversion of parent drug to active metabolites (poor metabolizer)
Interferon IL28B Disease progression
Various antidepressants CYP2D6, CYP2C19 Rapid inactivation and elimination in ultrarapid metabolizers

Pharmacogenetics Definitions

Definitions of Pharmacogenetic Terms

Allele

Alternate form of a gene located on a specific chromosome

Chromosome

Linear bodies in the cell nucleus that contain most or all genes of the organism

Deletion

Absence of a section of genetic material from a gene or absence of 1 or more entire genes from a chromosome

Duplication

Part of a chromosome in which the genetic material, including an entire gene or genes, is repeated; or process of forming a duplication

Expression

Detectable effect of a gene, usually manifested by the amount and/or type of protein

Gene

Functional unit of heredity that occupies a specific locus on a chromosome; capable of reproducing itself exactly at each cell division; directs formation of an enzyme or other protein

Genotype

Genetic constitution of an individual gene; may reflect a single nucleotide polymorphism, mutation, or series of variants

Haplotype

Group of genetic variants from 1 or more genes (eg, of the major histocompatibility complex) located on a single chromosome; usually closely enough linked to be inherited as a unit or characteristic pattern

Heterozygote

2 genes at corresponding loci on homologous chromosomes different for 1 or more loci; 2 different copies

Homozygote

2 genes at corresponding loci on homologous chromosomes identical for 1 or more loci; 2 identical copies

Insertion

Section of genetic material inserted into an existing gene sequence

Linkage

Relationship between genes on the same chromosome that causes them to be inherited together

Metabolizers

Poor metabolizer; lacks capacity (partially or almost totally) to metabolize a medication through a specific pathway

Intermediate metabolizer; has less than normal capacity to metabolize a medication through a specific pathway

Ultrarapid metabolizer; has enhanced capacity to metabolize a medication through a specific pathway

Extensive metabolizer; has normal population-based capacity to metabolize a medication through a specific pathway

Mutant

Change in hereditary material involving either a physical change in chromosome relations or a biochemical change in the codons that make up genes that are associated with a phenotype

Pharmacodynamics

The response of the body to a drug (eg, positive vs. negative response)

Pharmacokinetics

Study of how a patient's body processes a drug based on genetics (eg, metabolic activation or inactivation of a drug)

Phenotype

Observable properties of an organism that are produced by the interaction between the genotype and environment

Single nucleotide polymorphism

Naturally occurring substitution of a single nucleotide at a given location in the genome of an organism, often resulting in phenotypic variability

Variant

Exhibiting variation or diversity, either genotypically or phenotypically

Wild type

Phenotype, genotype, or gene that predominates in a natural population of organisms or strain of organisms in contrast to that of mutant forms

Specific Drug-Gene Pair Examples and Associated Tests

Pharmacogenetic testing can be performed by interrogating targeted genetic variants or by phenotype testing (eg, to evaluate enzyme function, protein expression, or concentrations of drugs and drug metabolites in biological specimens). The following tables show examples of drug-gene pairs and actions when variants are detected.

5-Fluorouracil (5-FU) (eg, Adrucil, Xeloda, Uftoral)

DPYD Genea

ARUP Test Indications Action When Variant(s) Are Detected

Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants 2012166

Predicts risk of dose-related toxicity to 5-FU therapy

Lower dose or alternate drug

aFor more information, refer to the CPIC Guideline for Fluoropyrimidines and DPYD. 

Abacavir (Ziagen)

HLA-B*57:01 Genea

ARUP Test Indications Action When Variant(s) Are Detected

HLA-B*57:01 for Abacavir Sensitivity 2002429

Standard of care before abacavir therapy per FDA

Predicts risk of abacavir hypersensitivity syndrome

Relevant to most populations

Alternate drug

aFor more information, refer to the CPIC Guideline for Abacavir and HLA-B. 

Allopurinol (Zyloprim)

HLA-B*58:01 Genea

ARUP Test Indications Action When Variant(s) Are Detected

HLA- B*58:01 Genotyping, Allopurinol Hypersensitivity 3001393

Predicts risk of developing SCARs, including SJS and TEN

Most relevant for Asian populations

Alternate drug

aFor more information, refer to the CPIC Guideline for Allopurinol and HLA-B. 

SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis

Antidepressants (eg, TCAs Such as Nortriptyline; SSRIs Such as Paroxetine)

CYP2D6, CYP2C19 Genesa

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assesses genetic variants that can contribute to risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5

Predicts extremes of metabolism that can lead to excess parent drug (poor metabolizers) or excess metabolite (ultrarapid metabolizers)

May aid in drug selection and dose planning for many drugs

Dose adjustment or alternate drug

CYP2C19 3001508

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP219

May aid in drug selection and dose planning for drugs metabolized by CYP219

Dose adjustment or alternate drug

CYP2D6 3001513

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2D6

May aid in drug selection and dose planning for drugs metabolized by CYP2D6

Dose adjustment or alternate drug

aFor more information, refer to the CPIC Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19  and the CPIC Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19. 

SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant

Atazanavir (Reyataz)

UGT1A1 Genea

ARUP Test Indications Action When Variant(s) Are Detected

UGT1A1 Sequencing 3001755

Can be used when prescribing atazanavir to assess likelihood of bilirubin-related discontinuation

Alternate drug

UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332

Can be used when prescribing atazanavir to assess likelihood of bilirubin-related discontinuation

Alternate drug

aFor more information, refer to the CPIC Guideline for Atazanavir and UGT1A1. 

Clopidogrel (Plavix)

CYP2C19 Genea

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5

Predicts extremes of metabolism that can lead to excess parent drug (poor metabolizers) or excess metabolite (ultrarapid metabolizers)

May aid in drug selection and dose planning for many drugs

Alternate drug

CYP2C19 3001508

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP219

May aid in drug selection and dose planning for drugs metabolized by CYP219

Alternate drug

aFor more information, refer to the CPIC Guideline for Clopidogrel and CYP2C19. 

 

Codeine, Tramadol, Oxycodone

CYP2D6 Genea

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5

Predicts extremes of metabolism that can lead to excess parent drug (poor metabolizers) or excess metabolite (ultrarapid metabolizers)

May aid in drug selection and dose planning for many drugs

Alternate drug

CYP2D6 3001513

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2D6

May aid in drug selection and dose planning for drugs metabolized by CYP2D6

Alternate drug

aFor more information, refer to the CPIC Guideline for Codeine and CYP2D6. 

Mayzent (Siponimod)

CYP2C9 Genea

ARUP Test Indications Action When Variant(s) Are Detected
CYP2C8 and CYP2C9 3001501

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C8 and CYP2C9

May aid in drug selection and dose planning for drugs metabolized by CYP2C8 and CYP2C9
Dose adjustment or alternate drug

aFor more information, refer to the FDA package insert for Mayzent. 

 

Phenytoin (eg, Phenytek, Dilantin)

CYP2C9 Genea

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5

Predicts extremes of metabolism leading to excess parent drug (poor metabolizers) or excess metabolite (ultrarapid metabolizers)

May aid in drug selection and dose planning for many drugs

Dose adjustment

CYP2C8 and CYP2C9 3001501

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C8 and CYP2C9

May aid in drug selection and dose planning for drugs metabolized by CYP2C8 and CYP2C9

Dose adjustment

aFor more information, refer to the CPIC Guideline for Phenytoin and CYP2C9 and HLA-B. 

Phenytoin, Carbamazepine, Lamotrigine

HLA-B*15:02 Genea

ARUP Test Indications Action When Variant(s) Are Detected

HLA-B*15:02 Genotyping, Carbamazepine Hypersensitivity 2012049

Identifies patients before treatment with carbamazepine who may be at risk for developing SJS or TEN

Recommended for patients not currently taking carbamazepine

Genetically high-risk populations include those in which HLA-B*15:02 is common (predominantly those with Asian ancestry)

Alternate drug

aFor more information, refer to the CPIC Guideline for Carbamazepine and HLA-B. 

Tacrolimus (eg, Protopic, Prograf)

CYP3A5 Gene

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5

Predicts extremes of metabolism leading to excess parent drug (poor metabolizers) or excess metabolite (ultrarapid metabolizers)

May aid in drug selection and dose planning for many drugs

Dose adjustment

CYP3A4 and CYP3A5 3001518

Assesses genetic risk of abnormal drug metabolism for drugs metabolized by CYP3A4 and CYP3A5

May aid in drug selection and dose planning for drugs metabolized by CYP3A4 and CYP3A5

Dose adjustment

 

Thiopurine

TPMT, NUDT15 Genesa

ARUP Test Indications Action When Variant(s) Are Detected

TPMT and NUDT15 3001535

Genotype test to assess risk, due to genetics, for severe myelosuppression with standard dosing of thiopurine drugs

Use for individuals being considered for thiopurine therapy or with a history of an adverse reaction to thiopurine therapy

Preferred test for patients with recent heterologous blood transfusion

Can be performed irrespective of thiopurine therapy

Lower dose or alternate drug

Thiopurine Methyltransferase, RBC 0092066

Phenotype test to assess risk for severe myelosuppression with standard dosing of thiopurine drugs

Use for individuals being considered for thiopurine therapy

Must be performed before thiopurine therapy is initiated

Can also detect rapid metabolizer phenotype

Lower dose or alternate drug

aFor more information, see the CPIC Guideline for Thiopurines and TPMT. 

ARUP Laboratory Tests

Genetic Testing

Enzyme Function Testing

Medical Experts

Contributor

McMillin

Gwendolyn A. McMillin, PhD
Professor of Clinical Pathology, University of Utah
Scientific Director, Mass Spectrometry Platform; Medical Director, Clinical Toxicology and Pharmacogenomics, ARUP Laboratories

References

  1. PharmGKB

    Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group, Canadian Pharmacogenomics Network for Drug Safety. PharmGKB. Stanford, CA. [Accessed: Jun 2020]

    Online
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