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Association for Molecular Pathology Releases CYP3A4 and CYP3A5 Genotyping Recommendations

NEW YORK – The Association for Molecular Pathology has published guidelines for designing, validating, and standardizing CYP3A4 and CYP3A5 genotyping assays across different laboratories.

The recommendations were published in the Journal of Molecular Diagnostics last week and extend earlier guidelines for clinical genotyping of TPMT, NUDT15, CYP2C19, CYP2C9, CYP2D6, and genes related to warfarin testing.

They are meant to be implemented together with other relevant clinical guidelines, such as those issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG), which both focus largely on PGx test interpretation and therapeutic recommendations for specific drug–gene pairs.

"The human cytochrome P450 family 3 subfamily A (CYP3A) serves an important role in the metabolic transformation of approximately 50 percent of marketed drugs, including fentanyl, midazolam, quetiapine, paclitaxel, statins, and other immunosuppressants," Victoria Pratt, chair of the AMP PGx Working Group, said in a statement.

CYP3A4 is abundantly expressed in the liver and small intestine and contributes significantly to drug metabolism. Variants of this gene are associated with drug response to quetiapine, an antipsychotic sometimes used to treat schizophrenia and bipolar disorder. Seroquel XR and Seroquel are common brand names for quetiapine.

CYP3A5 is expressed in approximately 10 to 20 percent of people with European ancestry and has a strong association with the immunosuppressant tacrolimus, which is often used in recipients of organ transplants under the common brand names of Protopic, Envarsus XR, Prograf, and Astagraf XL.

The AMP Pharmacogenetics Working Group used a two-tier strategy for selecting PGx variants to recommend for clinical testing. Tier 1 recommended alleles are those that have a well-characterized effect on the function of the protein or gene expression, an appreciable minor allele frequency (MAF) within a population or genetic ancestry group, publicly available reference materials, and are technically feasible for clinical laboratories to assay using standard molecular testing methods. Tier 2 recommended variant alleles include those that have a well-characterized function or appreciable MAF but do not meet all tier 1 criteria, although they may be upgraded to tier 1 should the appropriate information or advances in testing technology become available.

CYP3A4 and CYP3A5 alleles recommended for tier 1 are CYP3A4*22, CYP3A5*3, CYP3A56, and CYP3A57.

No CYP3A5 alleles and only the CYP3A4*20 allele were recommended for tier 2.

"As the molecular diagnostic landscape evolves, AMP is committed to sharing our expertise and collaborating with the broader laboratory community to continuously improve professional PGx practices for CYP3A4 and CYP3A5as well as many other common genotyping assays," Pratt said.