NEW YORK (GenomeWeb) – The Association for Molecular Pathology this week published consensus, evidence-based recommendations to assist lab professionals in designing and validating clinical CYP2C19 assays. The recommendations are the association's first of many planned recommendations related to pharmacogenetics testing.
"We started with the easiest one. We realized that for some of the other ones that we are going to tackle there may not be commercial platforms available for those assays or there may be differences in our recommendations from some commercial platforms when they are available. This is just the first one in a list to do," said Victoria Pratt, associate professor of medical and molecular genetics at Indiana University School of Medicine and AMP pharmacogenetics working group chair.
Pratt declined to identify which gene may be studies next, but said the working group plans to evaluate as many pharmacogenetics genes as possible.
The recommendations for the cytochrome P450 2C19 gene, known as CYP2C19, focus on allele selection used in testing. CYP2C19 is one of the most frequently tested pharmacogenetics genes because it is involved in phase 1 metabolism of many commonly prescribed medications. Packaging for the anti-platelet drug Plavix, for example, contains a warning that patients with diminished CYP2C19 function, or poor metabolizers of the drug, are at greater risk of cardiovascular adverse events after acute coronary syndrome or percutaneous coronary intervention than normal metabolizers of Plavix. The recommendations were published last week in The Journal of Molecular Diagnostics.
AMP recommended two tiers of allele selection for designing CYP2C19 genotyping assays, using criteria such as allele function, population frequency, and availability of reference materials, according to Pratt.
"There is a minimum standard which everyone should meet, and then we looked at an expansion, or Tier 2, where we felt there was also good evidence for the alleles, but those alleles may be rare in the population," Pratt said. "There was also a high degree of confidence in the function of the alleles, so that is why we included a Tier 2."
The Tier 1 allele selection recommendations include the CYP2C19 alleles *2, *3, and *17, which are already tested in most, if not all, commercial platforms. CYP2C19*2 and CYP2C19*3 are known as no-function alleles, which would make them poor metabolizers of certain drugs like Plavix, according to Pratt.
The CYP2C19*17 allele, by contrast, is associated with increased function. Certain proton pump inhibitors such as omeprazole, the active ingredient in Prilosec, used to treat gastroesophageal reflux disease, gastric ulcers and other acid-related disorders, may experience insufficient response to treatment with standard doses of the drug, according to Pratt.
The CYP2C19 alleles recommended for Tier 2 testing include *4A, *4B, *5, *6, *7, *8, *9, *10, and *35. These alleles have been shown to have decreased or no function, according to the AMP recommendations. While not as common in the general population, some of the Tier 2 alleles might be useful for testing certain ethic groups in which they are more common.
"For example, *4B is prevalent in the Ashkenazi Jewish population. One of the authors [of the recommendations] who is based in New York does a lot of testing in that population and includes that allele in testing," Pratt said.
AMP began studying pharmacogenetics genotyping allele selection to improve standardization, according to Pratt.
"We are hoping that it helps improve standardization around the US and abroad for those people doing pharmacogenetics testing," she said.
There are currently no professional recommendations on which variants to include in clinical pharmacogenetics tests, according to the AMP report. A 2016 study of pharmacogenetic assays conducted by the Centers for Disease Control and Prevention's Genetic Testing Reference Material Program, or GeT-RM, found that variants were not consistent between panels.
A similar study of challenges in ordering and interpreting pharmacogenetics tests, published in The American Journal of Medicine last year, found similar inconsistencies, based on surveys of laboratories offering pharmacogenetics services for CYP2D6 and CYP2C19 genotyping. That study found different combinations of variants were used to define haplotypes and results were reported using different nomenclature systems. These variations could alter test interpretation and patient care, authors of the AMP recommendations wrote.
"Standardized PGx test panels could enable physicians, pharmacists, researchers, and other stakeholders to understand PGx test results without extensive scrutiny of the alleles included in the assay, and provide assurance that clinical laboratory panels include a minimum set of clinically relevant PGx alleles," the recommendations state.
AMP's efforts to define attributes of pharmacogenetic gene alleles and recommend alleles for clinical testing is somewhat modeled after recommendations of a panel of variants for cystic fibrosis carrier screening developed by the American College of Medical Genetics and Genomics and the American College of Obstetricians and Gynecologists in 2001 and 2004, according to Pratt and the AMP report. A major difference, is that there is more information currently available for CYP2C19 allele selection than there was when the cystic fibrosis work was being done, according to Pratt, who also worked on the cystic fibrosis panel recommendations.
"When we did cystic fibrosis, there were a very limited number of platforms that were available and none of them were FDA approved," Pratt said. "We have more data. We have more ethnic data. We have more data on the alleles and the frequencies in the population. We have more data on the functionality of the alleles. We have reference materials for each of the alleles in our recommendation, so we have a lot more information than when I was involved in cystic fibrosis a long time ago."
AMP plans to review and update the CYP2C19 recommendations every few years as needed, Pratt said.