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AMP Working Group Recommends Alleles to Include in Warfarin Sensitivity Genotyping Assays

NEW YORK – An Association for Molecular Pathology working group has developed new guidelines for determining which alleles should be included in clinical genotyping assays that predict warfarin response. 

Clinical pharmacogenomic tests can vary from laboratory to laboratory and with these new guidelines and others it recently developed, AMP's PGx Working Group aims to standardize the alleles included in such assays for warfarin sensitivity. Determining a patient's warfarin dose can be difficult as it is influenced by genetic variants as well as age, body size, and other comorbidities, and genotyping has helped guide dosing for about a decade.

Members of the working group evaluated the functional effects, allele frequencies, and other technical considerations for a number of alleles tied to warfarin sensitivity. Through this, they generated a minimum set of alleles that should be included in genotyping tests, dubbed tier one, and an expanded set of alleles that are optional for inclusion, dubbed tier two.

"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," senior author Victoria Pratt from Indiana University School of Medicine and the chair of the AMP PGx Working Group said in a statement. "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." 

 They presented these guidelines Wednesday in the Journal of Molecular Diagnostics.

Pratt and the PGx Working Group evaluated genes that have previously been reported to affect patient sensitivity to warfarin or warfarin genes. They assessed alleles or variants in these genes based on three criteria: whether the allele or variant was well-characterized and how it affects drug response is known, how common it is within various populations, and whether reference materials for it are available. Alleles meeting all three criteria were placed in tier one, while those meeting one or two were placed in tier two.

Seven alleles were included in tier one, including six different CYP2C9 alleles. Cytochrome P450 2C9 belongs to the CYP2C subfamily of the cytochrome P450 enzymes and is a key metabolic enzyme not only for warfarin, but for other medications as well. Based on their criteria, the working group placed CYP2C9*2, *3, *5, *6, *8, and *11 in tier one.

The seventh allele in tier one was VKORC1 c.-1639G>A, which affects a promoter transcription factor binding site and leads to both lower VKORC1 gene and protein expression. It is common among East Asian as well as Caucasian and Middle Eastern populations and, to a lesser degree, among African and South or Central Asian populations.

Seven alleles fell in tier two, including three other CYP2C9, two other VKORC1 alleles, and a CYP4F2 allele.

This tier also includes a CYP2C cluster that a genome-wide association study uncovered in an African-American cohort. The rs12777823 variant has a minor allele frequency of 25 percent among African Americans and is found in other population groups, but is not associated with warfarin dose requirements in Caucasian, Japanese, or Egyptian patients. The allele may instead be in linkage disequilibrium with a functional variant found among people of West African ancestry, the researchers said.

These tiers, the PGx Working Group noted, are meant to be a reference guide to help standardize tests and may be updated as new data and reference material become available.

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