{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:31:03Z","timestamp":1789673463038,"version":"4.0.1"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>DPYD<\/jats:italic> gene encodes dihydropyrimidine dehydrogenase, the rate\u2010limiting enzyme for the metabolism of fluoropyrimidines 5\u2010fluorouracil and capecitabine. Genetic variants in <jats:italic>DPYD<\/jats:italic> 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\u20105923C&gt;G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G&gt;A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single\u2010nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G&gt;A is often utilized as a proxy for the function\u2010altering intronic variant. Clinical genotyping of <jats:italic>DPYD<\/jats:italic> identified a patient who had c.1236G&gt;A, but not c.1129\u20105923C&gt;G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G&gt;A, but not c.1129\u20105923C&gt;G, were identified in the Children's Mercy Data Warehouse and the <jats:italic>All of Us<\/jats:italic> Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G&gt;A can generate false\u2010positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that <jats:italic>DPYD<\/jats:italic> genotyping should include the functional variant c.1129\u20105923C&gt;G, and not the c.1236G&gt;A proxy, to accurately predict DPD activity.<\/jats:p>","DOI":"10.1111\/cts.13699","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T05:29:57Z","timestamp":1703222997000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Updated <i>DPYD<\/i><scp>HapB3<\/scp> haplotype structure and implications for pharmacogenomic testing"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0867-7545","authenticated-orcid":false,"given":"Amy J.","family":"Turner","sequence":"first","affiliation":[{"name":"RPRD Diagnostics LLC  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8998-2551","authenticated-orcid":false,"given":"Cyrine E.","family":"Haidar","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-5649","authenticated-orcid":false,"given":"Wenjian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3044-5521","authenticated-orcid":false,"given":"Erin C.","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Research Institute (CMRI)  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Offer","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7474-2339","authenticated-orcid":false,"given":"Philip E.","family":"Empey","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4279-9367","authenticated-orcid":false,"given":"Andrew","family":"Haddad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Pittsburgh School of Pharmacy  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Tahir","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin, School of Pharmacy  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2214-7981","authenticated-orcid":false,"given":"Gunter","family":"Scharer","sequence":"additional","affiliation":[{"name":"RPRD Diagnostics LLC  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Broeckel","sequence":"additional","affiliation":[{"name":"RPRD Diagnostics LLC  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-1893","authenticated-orcid":false,"given":"Andrea","family":"Gaedigk","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology &amp; Therapeutic Innovation Children's Mercy Research Institute (CMRI)  Kansas City Missouri USA"},{"name":"School of Medicine University of Missouri\u2010Kansas City  Kansas City Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/OP.20.00553"},{"key":"e_1_2_11_3_1","unstructured":"Clinical Pharmacogenetics Implementation Consortium (CPIC\u00ae).CPIC\u00ae Guideline for Fluoropyrimidines and DPYD Webpage. DPYD Allele Frequency table. Accessed September 11 2023.https:\/\/cpicpgx.org\/guidelines\/guideline\u2010for\u2010fluoropyrimidines\u2010and\u2010dpyd\/"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.02364"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.911"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-021-02385-x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2321"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.685"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29025"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv402"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2023.06.005"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31391"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.411"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1809937"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01031-z"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_11_18_1","unstructured":"All of Us Research Program.All of Us Genomic Quality Report webpage. Accessed September 11 2023.https:\/\/support.researchallofus.org\/hc\/en\u2010us\/articles\/4617899955092\u2010All\u2010of\u2010Us\u2010Genomic\u2010Quality\u2010Report\u2010"},{"key":"e_1_2_11_19_1","unstructured":"Hail.Hail\u2010Powered Science webpage. Accessed September 11 2023.https:\/\/hail.is\/references.html"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14742"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.02780"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-010-0879-3"},{"key":"e_1_2_11_23_1","unstructured":"National Library of Medicine National Center for Biotechnology Information.Medical Genetics Summaries [Internet] webpage. 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