Novel Polymorphisms Associated With Tacrolimus Trough Concentrations: Results From a Multicenter Kidney Transplant Consortium
Rattachement africain : us, Égypte. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
BACKGROUND: The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in whites relative to African Americans (AA). METHODS: We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single-nucleotide polymorphism chip with 2722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a seven-center consortium. RESULTS: During the 6-month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4-8.4) ng/mL vs. 8.3 (6.4-10.4) ng/mL (P<0.0001), despite 60% higher daily doses, 8 (5-10) mg vs. 5 (4-7) mg (P<0.0001). The median tacrolimus trough concentration in week 1 posttransplant was particularly low in AAs (2.1 [1.2-3.5] ng/mL) compared with non-AAs (5.0 [3.1-8.2] ng/mL) (P<0.0001), despite similar initial doses. In single-variant analysis, CYP3A5*3 (rs776746) was the top variant (P=2.4×10) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, 35 additional variants were identified (P<0.01, not significant at false discovery rate 20%). In the final multivariant, regression models beginning with these variants and clinical factors, seven variants were identified in the non-AA and seven variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations. CONCLUSION: We identified variants beyond CYP3A5*3, which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Novel Polymorphisms Associated With Tacrolimus Trough Concentrations: Results From a Multicenter Kidney Transplant Consortium
- Date Crossref
- 15/02/2011
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Minnesota Department of Experimental and Clinical Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Southern California Clinical and Translational Science Institute pays non établi dans la noticeStructure de recherche
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University of Alabama at Birmingham Division of Nephrology pays non établi dans la noticeUniversité ou école supérieure
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Hennepin County Medical Center Department of Medicine pays non établi dans la noticeÉtablissement de santé
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National Institute of Allergy and Infectious Diseases pays non établi dans la noticeStructure de recherche
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October 6 University Égypte (code pays fourni par la source)Université ou école supérieure
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College of Pharmacy Department of Experimental and Clinical Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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October 2010 pays non établi dans la noticeInstitution
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Supplemental digital content is available for this article. Direct URL citations appear in the printed text pays non établi dans la noticeInstitution
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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Disease or the National Institutes of Health pays non établi dans la noticeStructure de recherche
Department of Experimental and Clinical Pharmacology — University of Minnesota, Southern California Clinical and Translational Science Institute et Division of Nephrology — University of Alabama at Birmingham, avec 7 autres affiliations. Pays d’affiliation : Égypte.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.