{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:12:31Z","timestamp":1760145151892,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French Health Department","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]},{"name":"\u201cD\u00e9l\u00e9gation \u00e0 la Recherche Clinique et \u00e0 l\u2019Innovation, DRCI\u201d","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]},{"name":"Centre Hospitalier de Versailles, Versailles, France, by the Jean Bernard Association","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]},{"name":"\u201cCentre National de G\u00e9notypage\u201d (CNG, Institut de G\u00e9nomique, CEA)","award":["PHRC-I 2008"],"award-info":[{"award-number":["PHRC-I 2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription\/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5\u2032\/3\u2032 (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.<\/jats:p>","DOI":"10.3390\/pharmaceutics16060834","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T05:27:19Z","timestamp":1718861239000},"page":"834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients"],"prefix":"10.3390","volume":"16","author":[{"given":"Heriberto","family":"Bruzzoni-Giovanelli","sequence":"first","affiliation":[{"name":"Centre d\u2019Investigation Clinique, 1427 Inserm\/AP-HP, H\u00f4pital Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Habib","family":"Zouali","sequence":"additional","affiliation":[{"name":"Fondation Jean Dausset-Centre d\u2019\u00c9tude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mourad","family":"Sahbatou","sequence":"additional","affiliation":[{"name":"Fondation Jean Dausset-Centre d\u2019\u00c9tude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Maneglier","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie, Centre Hospitalier de Versailles, 78150 Le Chesnay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Michel","family":"Cayuela","sequence":"additional","affiliation":[{"name":"D\u00e9partement d\u2019H\u00e9matologie et Biologie Mol\u00e9culaire et EA3518, H\u00f4pital Saint-Louis, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1293-9686","authenticated-orcid":false,"given":"Angelita","family":"Rebollo","sequence":"additional","affiliation":[{"name":"UTCBS, INSERM U1267-CNRS UMR8258, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 4 Avenue de l\u2019Observatoire, CEDEX 06, 75270 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6380-6453","authenticated-orcid":false,"given":"Gustavo H.","family":"Marin","sequence":"additional","affiliation":[{"name":"CUFAR, Farmacologia B\u00e1sica, CONICET\u2014FCMLP, Universidad Nacional de La Plata, 60 & 120, La Plata 1900, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Geromin","sequence":"additional","affiliation":[{"name":"D\u00e9partement d\u2019H\u00e9matologie et Biologie Mol\u00e9culaire et EA3518, H\u00f4pital Saint-Louis, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carole","family":"Tomczak","sequence":"additional","affiliation":[{"name":"D\u00e9partement d\u2019H\u00e9matologie et Biologie Mol\u00e9culaire et EA3518, H\u00f4pital Saint-Louis, AP-HP, 75010 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Alberdi","sequence":"additional","affiliation":[{"name":"UMS Saint-Louis US53\/UAR2030, Institut de Recherche Saint Louis, Plateforme Technologique Centre Hayem, H\u00f4pital Saint-Louis, Universit\u00e9 Paris Cite\u2014INSERM\u2014CNRS, 1 Av Claude Vellefaux, CEDEX 10, 75475 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5358-4463","authenticated-orcid":false,"given":"Jean-Francois","family":"Deleuze","sequence":"additional","affiliation":[{"name":"Fondation Jean Dausset-Centre d\u2019\u00c9tude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, 75010 Paris, France"},{"name":"Centre National de Recherche en G\u00e9nomique Humaine, Institut Fran\u00e7ois Jacob, CEA, Universit\u00e9 Paris Saclay, CNRGH, 91190 Evry, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Rousselot","sequence":"additional","affiliation":[{"name":"D\u00e9partement d\u2019H\u00e9matologie, Centre Hospitalier de Versailles, 78157 Le Chesnay, France"},{"name":"UMR1184, D\u00e9partement IDMIT, Commissariat \u00e0 L\u2019\u00e9nergie Atomique et aux Energies Alternatives, Universit\u00e9 de Versailles Saint-Quentin-en-Yvelines Paris-Saclay, 92265 Fontenay-Aux-Roses, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1053\/j.seminhematol.2010.07.001","article-title":"Chronic Myeloid Leukemia: A Historical Perspective","volume":"47","author":"Goldman","year":"2010","journal-title":"Semin. 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