Journal article
Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing
Clinical and translational science, Vol.17(1), e13699
01/2024
DOI: 10.1111/cts.13699
PMCID: PMC10777430
PMID: 38129972
Abstract
The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate-limiting enzyme for the metabolism of fluoropyrimidines 5-fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129-5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single-nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function-altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129-5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129-5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false-positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129-5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.
Details
- Title: Subtitle
- Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing
- Creators
- Amy J TurnerCyrine E Haidar - St. Jude Children's Research HospitalWenjian YangErin C BooneSteven M Offer - Mayo ClinicPhilip E Empey - University of PittsburghAndrew Haddad - University of PittsburghSaba Tahir - Medical College of WisconsinGunter ScharerUlrich Broeckel - Medical College of WisconsinAndrea Gaedigk - Children’s Mercy Research Institute
- Resource Type
- Journal article
- Publication Details
- Clinical and translational science, Vol.17(1), e13699
- DOI
- 10.1111/cts.13699
- PMID
- 38129972
- PMCID
- PMC10777430
- NLM abbreviation
- Clin Transl Sci
- ISSN
- 1752-8054
- eISSN
- 1752-8062
- Grant note
- OT2 OD026555 / NIH HHS OT2 OD026557 / NIH HHS OT2 OD025315 / NIH HHS OT2 OD026551 / NIH HHS OT2 OD026553 / NIH HHS OT2 OD025276 / NIH HHS OT2 OD026549 / NIH HHS OT2 OD025337 / NIH HHS OT2 OD023205 / NIH HHS U24 OD023121 / NIH HHS U24 OD023163 / NIH HHS OT2 OD026556 / NIH HHS OT2 OD026554 / NIH HHS OT2 OD026550 / NIH HHS OT2 OD026548 / NIH HHS OT2 OD026552 / NIH HHS OT2 OD025277 / NIH HHS U2C OD023196 / NIH HHS OT2 OD023206 / NIH HHS U24 OD023176 / NIH HHS
- Language
- English
- Date published
- 01/2024
- Academic Unit
- Pathology
- Record Identifier
- 9984618636602771
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