Germline Pharmacogenetics - PGx

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Indications for Testing

  • Provide pre-therapeutic guidance for drug and dose selection
  • Evaluate whether an adverse drug reaction (ADR), non-standard dose requirement, or therapeutic failure could be explained by known 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
    • Investigate potential genetic causes for an adverse drug reaction (ADR), therapeutic failure, or nonstandard dose requirements
    • Familial testing may be appropriate
      • Testing options should be discussed with laboratory or genetic counselor
  • Monitoring drug therapy and dosing is accomplished through clinical exam, biomarkers, and/or determining concentrations of drugs and drug metabolites in biological specimens; monitoring tools are drug- and patient-specific
  • 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. Germline pharmacogenetics can explain and predict variations in both pharmacokinetic and pharmacodynamic processes.

The goals of pharmacogenetic testing are to reduce the high number of nonresponders (averaging 30-60% of patients), reduce adverse drug reactions, and optimize dosing.

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.

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 by this panel

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 variants 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

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

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

Limitations 

Alleles other than HLA-B*57:01 will not be evaluated

Does not distinguish between heterozygote and homozygote carriers

Diagnostic errors can occur due to rare sequence variations

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

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

HLA-B*15:02 Genotyping, Carbamazepine Hypersensitivity 2012049
Method: Polymerase Chain Reaction/Sequence Specific Oligonucleotide Probe Hybridization

Limitations 

Negative result for HLA-B*15:02 does not replace the need for therapeutic drug or other clinical monitoring

Absence of risk allele does not exclude development of other types of CBZ hypersensitivity, such as CBZ-induced MPE or HSS

Other genetic or nongenetic factors that may affect hypersensitivity to CBZ are not identified

Rare, undocumented alleles may occur that may or may not give false-positive results

CBZ therapy should be discontinued in all individuals if symptoms of SJS or TEN develop, regardless of HLA-B*15:02 status 

Statin Sensitivity SLCO1B1, 1 Variant 2008426
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only the targeted SLCO1B1 variant will be analyzed

Diagnostic errors can occur due to rare sequence variations

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

Genetic testing does not replace the need for therapeutic or clinical monitoring 

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 by this test

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 

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

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

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

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

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

Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC, Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012; 91(2): 321-6. 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 AM, van Kuilenburg AB, van Schaik RH, 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 2016]

Fonseca F, de la Torre R, Díaz L, Pastor A, Cuyàs E, Pizarro N, Khymenets O, Farré M, Torrens M. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response PLoS One. 2011; 6(5): e19527. PubMed

Gervasini G, Benítez J, Carrillo JA. 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

Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain Pharmacology. 2011; 87(5-6): 274-85. 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]

Lurcott G. The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives, hydrocodone and oxycodone Anesth Prog. 1998; 45(4): 154-6. PubMed

McMillin G, Wadelius M, Pratt V. Pharmacogenetics. Accepted, 2015 to Rifai N and Wittwer C (Eds). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 6th ed.. St. Louis, MO: Elsevier Saunders, 2015.

McMillin G. Pharmacogenetics, Ch 43. In Burtis CA, Ashwood ER and Burns DE (Eds). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th ed. St Louis, MO: Elsevier Saunders, 2012.

McMillin G. Pharmacogenetics. Accepted, 2016 to Clarke W (Ed). Contemporary Practice in Clinical Chemistry , 3rd ed. American Association for Clinical Chemistry, 2016.

McMillin G. Pharmacogenetics. In Burtis CA and Bruns DE (Eds). Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 7th ed. St. Louis, MO: Elsevier Saunders, 2015.

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

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

Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier MF, Hochstrasser D, Dayer P, Desmeules JA. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety Br J Pharmacol. 2010; 160(4): 919-30. PubMed

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

Kalman LV, Agúndez J, Appell L, Black JL, Bell GC, Boukouvala S, Bruckner C, Bruford E, Caudle K, Coulthard SA, Daly AK, Del Tredici A, Dunnen JT, Drozda K, Everts RE, Flockhart D, Freimuth RR, Gaedigk A, Hachad H, Hartshorne T, Ingelman-Sundberg M, Klein TE, Lauschke VM, Maglott DR, McLeod HL, McMillin GA, Meyer UA, Müller DJ, Nickerson DA, Oetting WS, Pacanowski M, Pratt VM, Relling MV, Roberts A, Rubinstein WS, Sangkuhl K, Schwab M, Scott SA, Sim SC, Thirumaran RK, Toji LH, Tyndale RF, van Schaik R, Whirl-Carrillo M, Yeo K, Zanger UM. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting Clin Pharmacol Ther. 2016; 99(2): 172-85. PubMed

Lee CC, McMillin GA, Babic N, Melis R, Yeo KJ. Evaluation of a CYP2C19 genotype panel on the GenMark eSensor® platform and the comparison to the Autogenomics Infiniti™ and Luminex CYP2C19 panels Clin Chim Acta. 2011; 412(11-12): 1133-7. PubMed

McMillin GA, Vazquez SR, Pendleton RC. Current challenges in personalizing warfarin therapy. Expert Rev Clin Pharmacol. 2011; 4(3): 349-62. PubMed

Melis R, Fauron C, McMillin G, Lyon E, Shirts B, Hubley LM, Slev PR. Simultaneous genotyping of rs12979860 and rs8099917 variants near the IL28B locus associated with HCV clearance and treatment response. J Mol Diagn. 2011; 13(4): 446-51. 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

Powers JL, Buys SS, Fletcher D, Melis R, Johnson-Davis K, Lyon E, Malmberg EM, McMillin GA. Multi-gene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19 and ABCB1 J Clin Pharmacol. 2016; 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: August 2016