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 lack of therapeutic benefit. The goals of pharmacogenetic testing are to reduce the high number of nonresponders (averaging 30-60% of patients) and to prevent or reduce adverse drug reactions.

ARUP offers single gene testing with predicted pharmacogenetic phenotypes as well as a genotype panel that codes for drug metabolizing enzymes. The panel includes a comprehensive report of drug recommendations and access to a medication risk management tool.

Quick Answers for Clinicians

When should pharmacogenetic testing be performed?

Pharmacogenetic testing may 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 (roughly 30-60% of patients), and prevent or reduce adverse drug reactions. Pharmacogenetic testing may also be relevant when investigating an adverse drug reaction or therapeutic failure.

Should I order testing for one gene or several genes?

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

How should results be interpreted?

Depending upon 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 section Examples of Specific Drug-Gene Pairs/Associated Tests below 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 adverse drug reactions/toxicity

Guiding Drug and Dose Selection

Adverse drug reactions (ADRs) include both therapeutic failure and potentially life-threatening toxicities. ADRs are classified as Type 1 (dose dependent) and Type 2 (not dose dependent). Both reactions require exposure to the drug for an ADR to occur. Some drugs (eg, phenytoin) are associated with both Type 1 and Type 2 ADRs. Pharmacogenetics can also be used to predict optimal dosing for select drugs.

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 whether the active drug accumulates instead of being eliminated as expected. Target dose of drug can be adjusted to compensate for differences in active drug accumulation and elimination, thereby minimizing or preventing type 1 ADRs.

​To guide 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).

ADR toxicity graphic

There are two mechanisms for reducing the amount of available active drug: through transport of a drug away from the site of action (eg, simvastatin and SLCO1B1), or through 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 inactivated form. Metabolic reactions can also change an inactive drug to an active drug, or change an active drug to another active drug.

The associations between how a gene variant affects the 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, regardless of dose; therefore, patients at risk of a type 2 reaction are advised to avoid drugs that could trigger the reaction. Examples include abacavir and HLA-B*5701 as well as carbamazepine or phenytoin and HLA-B*1502. In both of these examples, patients who carry at least one affected HLA-B allele are at risk of the associated ADR and should avoid the associated 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 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 the popular anticoagulant drug, warfarin. Several other algorithms have also been developed for warfarin.

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

Additional Dosing Guidelines

Monitoring for Therapeutic Failure

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

Posttherapeutic evaluation of adverse drug reactions or failure to respond is dependent on

  • Clinical factors
  • Clinical scenario (eg, whether a reaction is likely to be related to the drug and/or dose administered)
  • Compliance
  • Drug
  • 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 containing 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 occupying 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

Pharmacokinetics

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

Pharmacodynamics

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

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

Examples of Specific Drug-Gene Pairs/Associated Tests

Pharmacogenetic testing can be performed by interrogating targeted genetic variants or by phenotype testing (eg, 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 Gene

ARUP Test Indications Action When Variant(s) Are Detected

Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants 2012166

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

Lower dose or alternate drug

Guideline: https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/
Abacavir (Ziagen)

HLA-B*57:01 Gene

ARUP Test Indications Action When Variant(s) Are Detected

HLA-B*57:01 for Abacavir Sensitivity 2002429

Standard of care prior to abacavir therapy per FDA. Predict risk of abacavir hypersensitivity syndrome. Relevant to most populations.

Alternate drug

Guideline: https://cpicpgx.org/guidelines/guideline-for-abacavir-and-hla-b/
Allopurinol (Zyloprim)

HLA-B*58:01 Gene

ARUP Test Indications Action When Variant(s) Are Detected

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

Predict risk of developing severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Most relevant for Asian populations.

Alternate drug

Guideline: https://cpicpgx.org/guidelines/guideline-for-allopurinol-and-hla-b/

Antidepressants (eg, Tricyclic Antidepressants [TCAs] Such As Nortriptyline; Selective Serotonin Reuptake Inhibitors [SSRIs] Such As Paroxetine)

CYP2D6, CYP2C19 Genes

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assess genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5.

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 or alternate drug

CYP2C19 3001508

Assess 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

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

Guidelines: https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/ and https://cpicpgx.org/guidelines/guideline-for-selective-serotonin-reuptake-inhibitors-and-cyp2d6-and-cyp2c19/

Atazanavir (Reyataz)

UGT1A1 Gene

ARUP Test Indications Action When Variant(s) Are Detected

UGT1A1 Sequencing 3001755

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

Alternate drug

UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332

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

Alternate drug

Guideline: https://cpicpgx.org/guidelines/guideline-for-atazanavir-and-ugt1a1/

Clopidogrel (Plavix)

CYP2C19 Gene

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

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

Alternate drug

CYP2C19 3001508

Assess 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

Guideline: https://cpicpgx.org/guidelines/guideline-for-clopidogrel-and-cyp2c19/

Codeine, Tramadol, Oxycodone

CYP2D6 Gene

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

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

Alternate drug

CYP2D6 3001513

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

Guideline: https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/

Mayzent (Siponimod)

CYP2C9 Gene

ARUP Test Indications Action When Variant(s) Are Detected
CYP2C8 and CYP2C9 3001501 Assess 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
Guideline: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf

Phenytoin (eg, Phenytek, Dilantin)

CYP2C9 Gene

ARUP Test Indications Action When Variant(s) Are Detected

Cytochrome P450 Genotyping Panel 3001524

Assess genetic risk of abnormal drug metabolism for drugs metabolized by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5. 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 and CYP2C9 3001501

Assess 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

Phenytoin, Carbamazepine, Lamotrigine

HLA-B*15:02 Gene

ARUP Test Indications Action When Variant(s) Are Detected

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

Identify patients prior to treatment with carbamazepine (CBZ) 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 Asian ancestry).

Alternate drug

Guidelines: https://cpicpgx.org/guidelines/guideline-for-phenytoin-and-cyp2c9-and-hla-b/ and https://cpicpgx.org/guidelines/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

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

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

Thiopurine

TPMT, NUDT15 Genes

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 who have had 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

Guideline: https://cpicpgx.org/guidelines/guideline-for-thiopurines-and-tpmt/

Limitations of Drug-Gene Pair Tests

  • Only the targeted gene variants will be detected
  • Diagnostic errors can occur due to rare sequence variations
  • Risk of therapeutic failure or adverse reactions may be affected by genetic and nongenetic factors that are not detected by this test (eg, drug-drug interactions)
  • Heparin should be avoided; specimens collected with heparin-containing blood tubes may cause a test to fail
  • Variant detection does not replace the need for therapeutic drug and clinical monitoring

ARUP Lab 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. Executive Summary: AACC Laboratory Medicine Practice Guideline - Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients

    Jannetto PJ
    Bratanow NC
    Clark WA
    Hamill-Ruth RJ
    Hammett-Stabler CA
    Huestis MA
    Kassed CA
    McMillin GA
    Melanson SE
    Langman LJ
    Executive Summary: American Association of Clinical Chemistry Laboratory Medicine Practice Guideline - Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients
    Feb 2019
    Online
Additional Resources
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