Germline Pharmacogenetics - PGx

Content Review: June 2020 Last Update:

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 several genotyping panels. One of the cytochrome P450 panels 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 selection and dose decisions, reduce the overall number of nonresponders, 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 assessing an individual 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. These changes are based on recommendations by the Clinical Pharmacogenetics Implementation Consortium (CPIC) or are included in the U.S. Food and Drug Administration (FDA) drug product labels. 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 develop personalized therapeutics
  • Predict or explain variant pharmacokinetics and/or pharmacodynamics of specific drugs as evidenced by repeated adverse drug reactions (ADRs), such as treatment failures or drug-related toxicities

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 adjustments, first determine whether the risk of an ADR is due to the patient receiving too much of an active drug (toxicity) or not enough of an 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 an 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 convert an active drug into an inactive form. Metabolic reactions can also transform an inactive drug into an active drug or can change an active drug into another active drug.

The associations between the effect of a gene variant on the activity of a specific drug, the target therapeutic dose of that drug, and the likelihood of an ADR are applied in 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 these drugs.

Dose Optimization

Therapeutic or loading doses 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 both reducing the time required to achieve a therapeutic response to the anticoagulant drug, warfarin, and lowering 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 prescribing and dosing warfarin.

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 the standard dosing of phenytoin  be considered for a CYP2C9 intermediate metabolizer, and that a 50% reduction in the 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. 

Resources for Dosing Guidelines

Dosing guidelines for certain drugs are available from the CPIC  and the Pharmacogenomics Knowledgebase (PharmGKB). 

Monitoring for Therapeutic Failure

Drug therapy and dosing should be monitored by clinical exams, 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 Term 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

A type of mutation that involves the loss of one or more nucleotides from a segment of DNA; a deletion can involve the loss of any number of nucleotides, from a single nucleotide to an entire piece of a chromosome

Duplication

A type of mutation in which one or more copies of a DNA segment are produced; a duplication can be as small as a few bases or as large as a major chromosomal region

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

A physical grouping of genomic variants (or polymorphisms) that tend to be inherited together

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

A section of genetic material inserted into an existing gene sequence; an insertion can involve the addition of any number of nucleotides, from a single nucleotide to an entire piece of a chromosome

Linkage

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

Metabolizers

Poor metabolizer; lacks capacity (partially or completely) 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

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

Pharmacodynamics

Study of how a drug affects the body

Pharmacokinetics

Study of how the 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

A type of polymorphism involving the variation of a single base pair in the human genome

Gene variant

A permanent change in the DNA sequence

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-FU (eg, Adrucil, Xeloda, Uftoral)

DPYD Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants 2012166

Use to predict 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. 

5-FU, 5-fluorouracil

Abacavir (Ziagen)

HLA-B*57:01 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

HLA-B*57:01 for Abacavir Sensitivity 2002429

Standard of care before abacavir therapy per FDA

Use to predict 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 for Use Action When Variant(s) Are Detected

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

Use to predict risk of developing SCARs, including SJS and TEN

Most relevant for those of Asian descent

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 and Other Psychotropic Medications (eg, TCAs Such as Nortriptyline; SSRIs Such as Paroxetine)

CYP2D6, CYP2C19 Genesa

ARUP Test Indications for Use Action When Variant(s) Are Detected

Pharmacogenetics Panel: Psychotropics 3004471

Use to assess genetic variants that may inform selection and dosing of common and less common psychotropic medications

Test is appropriate for individuals with personal or family history of therapeutic failure or adverse events related to psychotropic medications

Dose adjustment or alternate drug

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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

Use to assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19

May aid in drug selection and dose planning for drugs metabolized by CYP2C19

Dose adjustment or alternate drug

CYP2D6 3001513

Use to assess 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 for Use Action When Variant(s) Are Detected

UGT1A1 Sequencing 3004386

Use to assess likelihood of bilirubin-related discontinuation of atazanavir

Alternate drug

UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332

Use to assess likelihood of bilirubin-related discontinuation of atazanavir

Alternate drug

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

Clopidogrel (Plavix)

CYP2C19 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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

Use to assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19

May aid in drug selection and dose planning for drugs metabolized by CYP2C19

Alternate drug

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

Codeine, Tramadol, Oxycodone

CYP2D6 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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

Use to assess 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 Opioids and CYP2D6, OPRM1, and COMT. 

Efavirenz (Sustiva)

CYP2B6 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

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

May aid in dose planning for many drugs

Dose adjustment

CYP2B6 3004310

Use to assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP2B6

May aid in dose planning for drugs metabolized by CYP2B6

Dose adjustment

aFor more information, refer to the CPIC Guideline for Efavirenz based on CYP2B6 genotype. 

Mayzent (Siponimod)

CYP2C9 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected
Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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
CYP2C8CYP2C9, and CYP2C cluster 3001501

Use to assess genetic risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2C8, CYP2C9, and the 2C cluster variant (rs12777823)

May aid in drug selection and dose planning for drugs metabolized by enzymes coded by CYP2C8, CYP2C9, and the 2C cluster variant (rs12777823)

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 for Use Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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, CYP2C9, and CYP2C cluster 3001501

Use to assess genetic risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2C8, CYP2C9, and the 2C cluster variant (rs12777823)

May aid in drug selection and dose planning for drugs metabolized by enzymes coded by CYP2C8, CYP2C9, and the 2C cluster variant (rs12777823)

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 for Use Action When Variant(s) Are Detected

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

Use to identify 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 in those of Asian descent)

Alternate drug

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

Simvastatin (Zocor)

SLCO1B1 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

SLCO1B1, 1 Variant 2008426

Use to identify individuals at increased risk for statin-related muscle toxicity

Dose limitations, monitoring, alternate drug

aFor more information, see the CPIC Guideline for statins and SLCO1B1, ABCG2, and CYP2C9. 

Tacrolimus (eg, Protopic, Prograf)

CYP3A5 Genea

ARUP Test Indications for Use Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Use to assess genetic variants that can contribute to the risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and the 2C cluster variant (rs12777823)

Use to predict 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

Use to assess 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

aFor more information, see the CPIC Guideline for Tacrolimus and CYP3A5. 

Thiopurine

TPMT, NUDT15 Genesa

ARUP Test Indications for Use Action When Variant(s) Are Detected

TPMT and NUDT15 3001535

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

Use in 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 in 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

References

  1. PharmGKB

    Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group, Canadian Pharmacogenomics Network for Drug Safety. PharmGKB. Accessed Jul 2022.

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