Pharmacogenetics - PGx

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Indications for Testing

  • Provide pre-therapeutic guidance for drug and dose selection
  • Provide post-therapeutic monitoring
    • Evaluate the cause of post-therapeutic adverse drug reactions or therapeutic failure
    • Optimize dose with pharmacokinetic or pharmacodynamic monitoring
  • Drug/gene associations

Laboratory Testing

  • Uses of pharmacogenetic testing for therapy management
    • Pre-therapeutic drug selection/avoidance
      • Predict risk of toxicity and likelihood of response that is dose-independent
    • Pre-therapeutic dose selection
      • Predict pharmacokinetics of a drug in order to optimize dosing frequency as well as determine best time to evaluate response to therapy (ie, estimate time to achieve steady state)
      • Select dose (eg, dose-escalate a patient that is predicted to have poor response or reduce dose for a patient that is predicted to be very sensitive to a drug)
      • Predict risk of toxicity and likelihood of response that is dose-dependent
    • Familial testing may be appropriate
      • Testing options should be discussed with laboratory or genetic counselor
  • Post-therapeutic evaluation of adverse drug reactions or failure to respond is dependent upon the following
    • Clinical factors
    • Clinical scenario (eg, whether a reaction is likely to be related to the drug and/or dose administered)
    • Compliance
    • Drug
    • Drug formulation

Genetic variations associated with drug response or drug disposition may predispose a patient to risk of drug-related toxicity or lack of therapeutic benefit and are referred to as pharmacogenetic variants. Pharmacogenetics can explain and predict variations in both pharmacokinetic and pharmacodynamic processes.

As such, pre-therapeutic pharmacogenetic testing to identify people who have inherited clinically significant variants may guide drug and dose selection to promote personalized therapeutics. Pharmacogenetic testing may be designed to detect human germline variants, somatic variants (eg, tumor tissue), or genomic variants of an infectious organism (eg, virus). The goals of pharmacogenetic testing are to reduce the high number of nonresponders (averaging 30-60% of patients) and to reduce adverse drug reactions.

Pharmacogenetics Definitions

Pathophysiology

  • Strengths and limitations of pharmacogenetic results are based on the following
    • Actual result (heterozygote vs mutant)
    • Allele frequency
    • Assay content
    • Clinically accepted guidelines
    • Drug choices available
    • Genotype/phenotype relationship
    • Methodology
    • Other factors that impact phenotype
      • Comedications
      • Clinical status
      • Age/sex
      • Alternate metabolic pathways
      • Other genes

Clinical Presentation

  • Pharmacogenetic variations

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 2007228
Method: Polymerase Chain Reaction/Single Nucleotide Extensions/Fragment Analysis

Limitations

Only targeted variants in the DPYD and TYMS genes are evaluated

Rare diagnostic errors may occur due to rare sequence variations

Genetic and/or non-genetic factors not detected by this test may affect 5-FU drug metabolism, efficacy, and risk for toxicity

Genotyping does not replace the need for therapeutic drug monitoring or clinical observation

Lack of detection of the targeted DPYD and TYMS variants does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU

Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants 2012166
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only targeted variants in DPYD gene will be detected

Rare diagnostic errors may occur due to rare sequence variations

Genetic and/or non-genetic factors not detected by this assay may affect 5-FU drug metabolism, efficacy, and risk for toxicity

Genotyping does not replace the need for therapeutic drug and clinical monitoring

Lack of detection of the targeted DPYD variants does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU

HLA-B*57:01 for Abacavir Sensitivity 2002429
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Diagnostic errors can occur due to rare sequence variations

Rare recombination events between HCP5 SNP rs2395029 and HLA-B*57:01 may occur

Nongenetic factors that may affect drug sensitivity are not identified

Testing for a genetic variant associated with ABC HSR does not replace the need for therapeutic drug or other clinical evaluation

Warfarin Sensitivity, CYP2C9 and VKORC1, 3 Variants 2012772
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only the targeted CYP2C9 and VKORC1 variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with warfarin may be affected by genetic and non-genetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

This test does not identify patients at risk for warfarin resistance 

Cytochrome P450 Genotype Panel 2013098
Method: Polymerase Chain Reaction/Primer Extension (CYP2D6)
Polymerase Chain Reaction/Fluorescence Monitoring (CYP2C9, CYP2C19, CYP3A5)

Limitations

Only the targeted CYP2D6, CYP2C9, CYP2C19, and CYP3A5  variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6, CYP2C9, CYP2C19, or CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Variant detection does not replace therapeutic drug and clinical monitoring

Cytochrome P450 2C9, CYP2C9 - 2 Variants 2012766
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only the targeted CYP2C9 variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2C9 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring 

Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Primer Extension

Limitations

Only the targeted CYP2D6 variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

It is not always possible to identify which allele is duplicated when a CYP2D6 duplication is detected

Cytochrome P450 2C19, CYP2C19 - 9 Variants 2012769
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only the targeted CYP2C19 mutations will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2C19 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

Cytochrome P450 3A5 Genotyping, CYP3A5, 2 Variants 2012740
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only the targeted CYP3A5 mutations will be detected

CYP3A5*7 is not analyzed by this test

Diagnostic errors can occur due to rare sequence variations

Phenotype predictions for transplant patients may require consideration of genotypes for both donor and recipient

Risk of therapeutic failure or adverse reactions with CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Pharmacogenetic testing does not replace the need for therapeutic drug or clinical monitoring

KRAS Mutation Detection 0040248
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Pyrosequencing- oncogenic mutations outside of codons 12, 13, and 61 will not be detected

A substantial portion of individuals with wild type KRAS still fail to respond to anti-EGFR agents, implicating downstream mutations

KRAS Mutation Detection with Reflex to BRAF Codon 600 Mutation Detection 2001932
Method: Polymerase Chain Reaction/Pyrosequencing

NRAS Mutation Detection by Pyrosequencing 2003123
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations

Limit of detection – 10% mutant alleles

Oncogenic mutations outside of codons 12, 13, and 61 will not be detected

Presence or absence of mutations does not guarantee a positive response or lack of response to anti-EGFR therapies or therapies targeted at downstream genes in the MAPK signaling pathway

UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations

Clinical significance of (TA)5 and (TA)8 is not well-established

Other variants such as those associated with Crigler-Najjar syndrome will not be detected

(TA)5 and (TA)8 are not detected

Other factors that contribute to irinotecan toxicity will not be detected

Pseudocholinesterase, Dibucaine Inhibition 0020159
Method: Quantitative Enzymatic

EGFR Mutation Detection by Pyrosequencing 2002440
Method: Polymerase Chain Reaction/Pyrosequencing

EGFR T790M Mutation Detection in Circulating Cell-Free DNA by Digital Droplet PCR 2012868
Method: Polymerase Chain Reaction

Limitations

Limit of detection – based upon amplifiable DNA, the limit of detection ranges from 0.5% to <0.01% mutant alleles

Optimal clinical testing intervals are unknown

Mutations other than EGFR T790M are not detected

Presence or absence of EGFR T790M does not guarantee a response to EGFR T790M-specific drug therapy 

Thiopurine Methyltransferase, RBC 0092066
Method: Enzymatic/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

Does not replace clinical monitoring

TPMT inhibitors may contribute to false-low test results

TPMT activity should be assessed prior to treatment with thiopurine drugs

Blood transfusion within 30 days will reflect donor status

Thiopurine Drug Metabolites 2011134
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

Limitations

Does not replace clinical monitoring

TPMT inhibitors may contribute to false-low test results

TPMT activity should be assessed prior to treatment with thiopurine drugs

TPMT testing – blood transfusion within 30 days will reflect donor status

Thiopurine Methyltransferase (TPMT) Genotyping, 4 Variants 2012233
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only targeted TPMT allele variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Genotyping in individuals who have received allogenic stem cell/bone marrow transplant will reflect donor status

Genotyping cannot distinguish the *1/*3A genotype from the *3B/*3C genotype

Thiopurine drug metabolism and risk for toxicity may be affected by genetic and nongenetic factors that are not evaluated by this test

Test does not assess for TPMT allele variants associated with ultra-high enzyme activity

Genotyping does not replace the need for therapeutic drug monitoring or clinical observation

Interleukin 28 B (IL28B)-Associated Variants, 2 SNPs 2004680
Method: Polymerase Chain Reaction/Single Nucleotide Extension

Limitations

SNPs other than those targeted will not be detected

Usefulness of the IL28B-associated SNPs for predicting therapy response for HCV genotypes other than HCV-1 is unknown; lack of favorable genetic factors should not be used to deny therapy

Mutations in genes and nongenetic factors that may affect response to HCV therapy are not detected

Diagnostic errors can occur due to rare sequence variation

Inosine Triphosphatase (ITPA) and Interleukin 28 B (IL28B)-Associated Variants, 4 SNPs 2006344
Method: Polymerase Chain Reaction/Single Nucleotide Extensions

Limitations

SNPs other than those targeted will not be detected

Usefulness of the IL28B-associated SNPs for predicting therapy response for HCV genotypes other than HCV-1 is unknown; lack of favorable genetic factors should not be used to deny therapy

Mutations in genes and nongenetic factors that may affect response to HCV therapy are not detected

Diagnostic errors can occur due to rare sequence variations

Related Tests

Guidelines

Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther. 2013; 94(6): 640-5. PubMed

General References

Amstutz U, Carleton BC. Pharmacogenetic testing: time for clinical practice guidelines. Clin Pharmacol Ther. 2011; 89(6): 924-7. PubMed

Becquemont L, Alfirevic A, Amstutz U, Brauch H, Jacqz-Aigrain E, Laurent-Puig P, Molina MA, Niemi M, Schwab M, Somogyi AA, Thervet E, van der Zee AMaitland-, van Kuilenburg ABp, van Schaik RHn, Verstuyft C, Wadelius M, Daly AK. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics. 2011; 12(1): 113-24. PubMed

Dosing Guidelines - CPIC. Manually curated by PharmGKB. Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group. Stanford, CA [Accessed: Aug 2015]

Gervasini G, Benítez J, Carrillo JAntonio. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. Eur J Clin Pharmacol. 2010; 66(8): 755-74. PubMed

Kitzmiller JP, Groen DK, Phelps MA, Sadee W. Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med. 2011; 78(4): 243-57. PubMed

List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). U.S. Food and Drug Administration. Silver Spring, MD [Accessed: Aug 2015]

McMillin G. Pharmacogenetics, Ch 43. In Burtis CA, Ashwood ER and Burns DE5. Fundamentals of Molecular Diagnostics, 5th ed. MO: Saunders, 2012.

McMillin G. Pharmacogenetics. In Bruns DE, Ashwood ER, Burtis CA. Tietz Fundamentals of Clinical Chemistry, 6th ed. St. Louis: WB Saunders, 2007.

Personalized Medicine Coalition. Personalized Medicine Coalition. Washington, DC [Accessed: Nov 2015]

Pharmacogenomics. Knowledge. Implementation. PharmGKB. Stanford, CA [Accessed: May 2015]

Table of Pharmacogenomic Biomarkers in Drug Labeling. U.S. Food and Drug Administration. Silver Spring, MD [Accessed: Aug 2015]

Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med. 2011; 364(12): 1144-53. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Borgman MP, Pendleton RC, McMillin GA, Reynolds KK, Vazquez S, Freeman A, Wilson A, Valdes R, Linder MW. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb Haemost. 2012; 108(3): 561-9. PubMed

Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein M, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin J, Kim H, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012; 107(2): 232-40. PubMed

Melis R, Lewis T, Millson A, Lyon E, McMillin GA, Slev PR, Swensen J. Copy number variation and incomplete linkage disequilibrium interfere with the HCP5 genotyping assay for abacavir hypersensitivity. Genet Test Mol Biomarkers. 2012; 16(9): 1111-4. PubMed

Profaizer T, Eckels D. HLA alleles and drug hypersensitivity reactions. Int J Immunogenet. 2012; 39(2): 99-105. PubMed

Whittington JE, Pham HD, Procter M, Grenache DG, Mao R. A patient with prolonged paralysis. Clin Chem. 2012; 58(3): 496-500. PubMed

Medical Reviewers

Last Update: April 2016