title: Multigene predictors of tacrolimus exposure in kidney transplant recipients.
abstract: OBJECTIVE
  Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition.
  
  
  METHODS
  We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008).
  
  
  RESULTS
  Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10(-75)). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated.
  
  
  CONCLUSIONS
  This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations. Original submitted 19 December 2014; Revision submitted 2 April 2015.
authors.affiliation: Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Pulk
authors.affiliation: Department of Nephrology & Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Schladt
authors.affiliation: Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, MN, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Nephrology & Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, MN, USA.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Israni
authors.affiliation: Division of Transplantation, Department of Surgery, University of Minnesota, MN, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, MN, USA.
authors.forename: Rory P
authors.initials: RP
authors.lastname: Remmel
authors.affiliation: Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*; D066027:Transplant Recipients
chemical_list: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016559:Tacrolimus; C000715087:ABCC2 protein, human; C000602470:POR protein, human; C510164:CYP3A5 protein, human
keywords: ABCC2; POR; calcineurin inhibitor; cytochrome P450 3A4 and 3A5; kidney transplant; pharmacogenomics; pharmacokinetics; tacrolimus