CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System

Yelena Ionova, James Ashenhurst, Jianan Zhan, Hoang Nhan, Cindy Kosinski, Bani Tamraz, Alison Chubb, Yelena Ionova, James Ashenhurst, Jianan Zhan, Hoang Nhan, Cindy Kosinski, Bani Tamraz, Alison Chubb

Abstract

Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-to-consumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 self-reported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

Conflict of interest statement

J.A., J.Z., H.N., C.K., and A.C. are employees of 23andMe, Inc. and hold shares and/or options of the company. All other authors declared no competing interests for this work.

© 2020 23andMe, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Proportion of individuals with at least one *2, *3, or *17 allele. Dark grey portion represents the percentage of each population carrying at least one clinically relevant CYP2C19 allele, that is *2, *3, or *17. Light grey portion is the percentage of each population that did not have a detected *2, *3, or *17 variant.
Figure 2
Figure 2
Percentage of University of California at San Francisco patients in each ethnic group who were prescribed one or more high‐pharmacogenetic‐risk CYP2C19 medications. A high‐pharmacogenetic‐risk medication is defined as a drug with an associated Clinical Pharmacogenetics Implementation Consortium or Dutch Pharmacogenetics Working Group genotype‐based prescribing guideline. Medications included in this study were clopidogrel, citalopram, escitalopram, sertraline, omeprazole, lansoprazole, pantoprazole, and voriconazole.
Figure 3
Figure 3
Number of University of California at San Francisco (UCSF) patients prescribed high‐pharmacogenetic‐risk CYP2C19 medications from June 2012 to September 2019, divided into two groups based on predicted CYP2C19 genotype. The dark grey bars represent the number of potential UCSF patients likely to have a clinically actionable CYP2C19 variant, as extrapolated from the genotype frequencies observed in the 23andMe cohort. The light grey bars represent the potential patients likely to be CYP2C19 normal metabolizers. The number of potential patients with a clinically relevant variant was calculated as follows: (total number of UCSF patients on the drug) * (percent of 23andMe research participants with one or more clinically relevant variant). The number of patients without a clinically relevant variant was calculated as follows: (total number of UCSF patients on the drug) * (percent of 23andMe research participants with an observed *1/*1 genotype). Note: Patients prescribed multiple high‐pharmacogenetic‐risk CYP2C19 medications are included in each respective drug group.

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