Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13699 |
| _version_ | 1797347349137195008 |
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| author | Amy J. Turner Cyrine E. Haidar Wenjian Yang Erin C. Boone Steven M. Offer Philip E. Empey Andrew Haddad Saba Tahir Gunter Scharer Ulrich Broeckel Andrea Gaedigk |
| author_facet | Amy J. Turner Cyrine E. Haidar Wenjian Yang Erin C. Boone Steven M. Offer Philip E. Empey Andrew Haddad Saba Tahir Gunter Scharer Ulrich Broeckel Andrea Gaedigk |
| author_sort | Amy J. Turner |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T11:46:29Z |
| format | Article |
| id | doaj.art-5ba0596362e44f6ea49932ac67879e47 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-08T11:46:29Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-5ba0596362e44f6ea49932ac67879e472024-01-24T18:33:50ZengWileyClinical and Translational Science1752-80541752-80622024-01-01171n/an/a10.1111/cts.13699Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testingAmy J. Turner0Cyrine E. Haidar1Wenjian Yang2Erin C. Boone3Steven M. Offer4Philip E. Empey5Andrew Haddad6Saba Tahir7Gunter Scharer8Ulrich Broeckel9Andrea Gaedigk10RPRD Diagnostics LLC Milwaukee Wisconsin USADepartment of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USADepartment of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USADivision of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute (CMRI) Kansas City Missouri USADepartment of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester Minnesota USADepartment of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh Pennsylvania USADepartment of Pharmaceutical Sciences University of Pittsburgh School of Pharmacy Pittsburgh Pennsylvania USAMedical College of Wisconsin, School of Pharmacy Milwaukee Wisconsin USARPRD Diagnostics LLC Milwaukee Wisconsin USARPRD Diagnostics LLC Milwaukee Wisconsin USADivision of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute (CMRI) Kansas City Missouri USAAbstract 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.https://doi.org/10.1111/cts.13699 |
| spellingShingle | Amy J. Turner Cyrine E. Haidar Wenjian Yang Erin C. Boone Steven M. Offer Philip E. Empey Andrew Haddad Saba Tahir Gunter Scharer Ulrich Broeckel Andrea Gaedigk Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing Clinical and Translational Science |
| title | Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing |
| title_full | Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing |
| title_fullStr | Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing |
| title_full_unstemmed | Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing |
| title_short | Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing |
| title_sort | updated dpyd hapb3 haplotype structure and implications for pharmacogenomic testing |
| url | https://doi.org/10.1111/cts.13699 |
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