The Association for Molecular Pathology (AMP) has published consensus recommendations designed to support the design, validation, and interpretation of clinical genotyping tests for the prediction of warfarin response. [Getty Images]

The Association for Molecular Pathology (AMP) today published consensus recommendations designed to support the design, validation, and interpretation of clinical genotyping tests for the prediction of warfarin response.

The new warfarin genotyping guideline offers a two-tier categorization of alleles that are recommended for inclusion in clinical PGx genotyping assays. Using criteria such as allele frequencies in different populations and ethnicities, the availability of reference materials and other technical considerations, the AMP PGx Working Group recommended a minimum set of alleles and their defining variants that should be included in all clinical warfarin sensitivity genotyping tests—what the guideline defines as Tier 1 PGx variant alleles.

The AMP PGx Working Group developed the guideline with organizational representation from the College of American Pathologists (CAP) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). The team also defined a Tier 2 list of optional alleles that do not currently meet one or more of the criteria for inclusion in Tier 1. AMP said the recommendations were meant to be a reference guide and not a restrictive list—and that it intends to update these recommendations as new data and/or reference materials become available.

Common benign variants in high linkage disequilibrium (LD) with established functional variant(s) are not currently being considered for inclusion as Tier 1 or Tier 2 variant alleles in routine clinical PGx genotyping panels, the Working Group added.

Guideline recommendations have been published in a manuscript, “Recommendations for Clinical Warfarin Sensitivity Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists,” that was released online ahead of publication in The Journal of Molecular Diagnostics.

“Clinical genotyping assays that help predict warfarin response and optimize a patient’s dosage requirements have enabled some of the earliest success stories of this precision medicine era,” said Victoria M. Pratt, Ph.D., FACMG, Professor and Director of Pharmacogenetics and Molecular Genetics Laboratories, Indiana University School of Medicine, and AMP PGx Working Group Chair.  “Together, the AMP PGx Working Group defined a standard set of evidence-based recommendations that will help build on these past successes and improve phenotype prediction and test interpretation for all future warfarin sensitivity genotyping panels.”

Earlier Recommendations

The AMP PGx Working Group previously developed recommendations for clinical CYP2C9 testing that were intended to be applied to CYP2C9-related medications including warfarin. Last year, the Working Group developed recommendations for clinical CYP2C9 testing that were intended to be applied to CYP2C9-related medications including warfarin.

Since then, the Working Group said, the discovery of additional well-characterized genes/alleles contributing to inter-individual variation in warfarin sensitivity created a need for a separate document addressing genes/alleles specifically related to warfarin sensitivity, including the CYP2C9 alleles.

CYP2C9 is a member of the CYP2C subfamily of the cytochrome P450 enzymes, and one of the most abundant and important drug metabolizing enzymes. It acts on approximately 15% of drugs in current clinical use, including ibuprofen and the blood thinner warfarin. As a result, it is currently included in the FDA’s Table of Pharmacogenetic Biomarkers in Drug Labeling for several FDA-approved drugs.

According to the Working Group, clinicians have been able since 2010 to obtain CYP2C9 and VKORC1 genotypes and use either the FDA prescribing label or PGx dosing algorithms to define warfarin dose requirements for their patients. While experts have contributed to establishing high-quality genotype-based recommendations for warfarin14 and the accessibility of clinical PGx testing continues to increase, the diversity of available testing platforms and variants interrogated have led to inconsistencies in results among labs.

“Although the initial CPIC guideline recommendations included variants that are more common among Caucasians and Asians, the updated 2017 guideline incorporated additional variants that are predictors of warfarin dose requirements in patients of African descent,” the Working Group noted. “In order to implement recommendations from the recent CPIC warfarin guideline, both the availability of self-reported ancestry and interrogation for specific alleles are therefore essential.”

“The Working Group recognizes that the benefit of genotype-guided dosing for warfarin to reduce under or over dosing episodes in patients from diverse ethnicities will not likely be realized unless testing panels account for appropriate clinical variants that are relevant for the ethnic groups to whom the test is offered,” the Group added.

The new guideline on clinical warfarin sensitivity genotyping allele selection is the last in a series of three reports that are intended to facilitate testing and promote standardization for frequently used pharmacogenetics (PGx) genotyping assays. The latest guideline builds on the earlier recommendations for clinical CYP2C19 and CYP2C9 genotyping, according to AMP.

The recommendations should be implemented together with other clinical guidelines such as those issued by the CPIC, which focus primarily on the interpretation of PGx test results and therapeutic recommendations for specific drug-gene pairs.

“AMP members are among the earliest adopters of pharmacogenetic testing in clinical settings,” said AMP President Karen E. Weck, M.D., who is also a Professor of Pathology and Laboratory Medicine, Professor of Genetics and Director, Molecular Genetics and Pharmacogenomics at University of North Carolina Chapel Hill, and a PGx Working Group Member. “This series of guidelines for common clinical PGx genotyping tests is another example of AMP’s ongoing commitment to sharing our collective expertise with the broader laboratory community in order to improve professional practice and patient care.”

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