Allele frequencies of two dihydropyrimidine dehydrogenase (DPYD) risk variants, c.1905+1G>A (*2A) and c.2846A>T (D949V), in a direct-to-consumer genetic database.

Abstract

2 Background: Pharmacogenetic (PGt) testing holds great potential for supporting clinical decision making and optimizing medication outcomes for cancer patients. Genetic variants in the DPYD gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity, and can cause severe fluoropyrimidine-related toxicity. However, the clinical uptake of PGt testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) PGt test will improve access to PGt testing. This study assessed the frequency of two DPYD variants, c.1905+1G > A (*2A) and c.2846A > T (D949V), in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped using Illumina genotyping arrays that included the DPYD c.1905+1G > A and c.2846A > T variants. Eligible subjects were 23andMe U.S. customers who were at least 18 years of age and consented to participate in research. IRB approval was obtained from Ethical & Independent Review Services. Results: Out of approximately 6.4 million eligible participants included in this analysis, the overall allele frequencies of DPYD c.1905+1G > A and c.2846A > T were 0.42% and 0.47%, respectively. People of Ashkenazi Jewish, South Asian, and European descent had the highest frequencies (0.56%, 0.56%, and 0.47%, respectively) for the DPYD c.1905+1G > A variant, and people of European and Hispanic/Latino descent had the highest frequencies (0.55% and 0.43%, respectively) for the DPYD c.2846A > T variant. Conclusions: This is the first description of an unselected cohort of individuals with DPYD c.1905+1G > A and c.2846A > T variants identified through DTC genetic testing. Preemptive DTC PGt testing can help disseminate potentially clinically useful information to a large number of consumers.

All You Need to Know About DPYD Genetic Testing for Patients Treated With Fluorouracil and Capecitabine: A Practitioner-Friendly Guide

“…Recently, 23andMe has preliminarily reported DPYD allele frequencies in 6,421,599 genotyped individuals of different ethnic backgrounds, such as European, Hispanic or Latino, African American, East Asian, Ashkenazi Jewish, South Asian, Middle Eastern, and others. 31 The allele frequency of *2A was 0.47%, 0.26%, 0.13%, 0.06%, 0.56%, 0.56%, 0.44%, and 0.34%, respectively. The allele frequency of p.D949V was 0.55%, 0.43%, 0.18%, 0.08%, 0.01%, 0.05%, 0.09%, and 0.27%, respectively.…”

“…it can be calculated that approximately 2% of the general population might have impaired DPD activity, conferring increased risk of FU and capecitabine toxicity 31. Interpretation of the results of DPYD genotyping.…”