{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:12:53Z","timestamp":1788307973014,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T00:00:00Z","timestamp":1644019200000},"content-version":"vor","delay-in-days":0,"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":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease\u2010related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross\u2010sectional, proof\u2010of\u2010concept association study to replicate the well\u2010established association between metoprolol concentrations and <jats:italic>CYP2D6<\/jats:italic> genotype\u2010inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and \u03b1\u2010hydroxymetoprolol (\u03b1\u2010OH\u2010metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400\u00a0mg (mean 84.3\u00a0\u00b1\u00a057.1\u00a0mg). CYP2D6\u2010inferred phenotype was significantly associated with both metoprolol and \u03b1\u2010OH\u2010metoprolol in unadjusted and adjusted models (all <jats:italic>p\u00a0<\/jats:italic>&lt;\u00a010<jats:sup>\u221214<\/jats:sup>). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.<\/jats:p>","DOI":"10.1111\/cts.13230","type":"journal-article","created":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T08:39:49Z","timestamp":1644050389000},"page":"1063-1073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof\u2010of\u2010concept study"],"prefix":"10.1111","volume":"15","author":[{"given":"Maxime","family":"Meloche","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"},{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e9goire","family":"Leclair","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Jutras","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa\u00efd","family":"Oussa\u00efd","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Jos\u00e9e","family":"Gaulin","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Mongrain","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Busseuil","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Claude","family":"Tardif","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"},{"name":"Faculty of Medicine Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Pierre","family":"Dub\u00e9","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"},{"name":"Faculty of Medicine Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"de Denus","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 de Montr\u00e9al  Montreal Quebec Canada"},{"name":"Montreal Heart Institute  Montreal Quebec Canada"},{"name":"Universit\u00e9 de Montr\u00e9al Beaulieu\u2010Saucier Pharmacogenomics Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2020.595219","article-title":"Pharmacogenetics guidelines: overview and comparison of the DPWG, CPIC, CPNDS, and RNPGx guidelines","volume":"11","author":"Abdullah\u2010Koolmees H","year":"2021","journal-title":"Front Pharmacol"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.96"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2000.106464"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2962"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3667"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3943"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.12.007"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12692"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1993.tb00411.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.193"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jhn.12272"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14034"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs-2016-0118"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2017.8"},{"key":"e_1_2_9_17_1","unstructured":"US Food and Drug Administration.Drug development and drug interactions: table of substrates inhibitors and inducers. Available:https:\/\/www.fda.gov\/drugs\/drug\u2010interactions\u2010labeling\/drug\u2010development\u2010and\u2010drug\u2010interactions\u2010table\u2010substrates\u2010inhibitors\u2010and\u2010inducers. Last updated March 6 2020. Accessed on September 9 2021."},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2354"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200208000-00007"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.07.002"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.081109"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.80"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05911"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0205-x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2008.4"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000433"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.234"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12643"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2017.17050550"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(19)30088-4"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2015.09.023"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0809171"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1907096"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14247"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.115.002031"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13230","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13230","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13230","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T13:59:18Z","timestamp":1692971958000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,5]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1111\/cts.13230"],"URL":"https:\/\/doi.org\/10.1111\/cts.13230","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,5]]},"assertion":[{"value":"2021-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}